Fused heterocyclic derivatives and methods of use

ABSTRACT

Selected compounds are effective for prophylaxis and treatment of diseases, such as HGF mediated diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving, cancer and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.

This application is a continuation-in-part of U.S. patent applicationSer. No. 11/879,034 filed Jul. 13, 2007 which claims benefit ofProvisional Application No. 60/830,882 filed Jul. 14, 2006 the entiretyof which is incorporated herein by reference.

FIELD OF THE INVENTION

This invention is in the field of pharmaceutical agents and specificallyrelates to compounds, compositions, uses and methods for treatingcancer.

BACKGROUND OF THE INVENTION

Protein kinases represent a large family of proteins, which play acentral role in the regulation of a wide variety of cellular processes,maintaining control over cellular function. A partial list of suchkinases includes ab1, Akt, bcr-ab1, Blk, Brk, Btk, c-kit, c-Met, c-src,c-fins, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10,cRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FGFR1,FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Frk, Fyn, Hck, IGF-1R,INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie,tie2, TRK, Yes, and Zap70. Inhibition of such kinases has become animportant therapeutic target.

The hepatocyte growth factor receptor (“c-Met”) is a unique receptortyrosine kinase shown to be overexpressed in a variety of malignancies.c-Met typically comprises, in its native form, a 190-kDa heterodimeric(a disulfide-linked 50-kDa α-chain and a 145-kDa β-chain)membrane-spanning tyrosine kinase protein (Proc. Natl. Acad. Sci. USA,84:6379-6383 (1987)). c-Met is mainly expressed in epithelial cells andstimulation of c-Met leads to scattering, angiogenesis, proliferationand metastasis. (See Cytokine and Growth Factor Reviews, 13:41-59(2002)).

The ligand for c-Met is hepatocyte growth factor (also known as scatterfactor, HGF and SF). HGF is a heterodimeric protein secreted by cells ofmesodermal origin (Nature, 327:239-242 (1987); J. Cell Biol.,111:2097-2108 (1990)).

Various biological activities have been described for HGF throughinteraction with c-met (Hepatocyte Growth Factor-Scatter Factor (HGF-SF)and the c-Met Receptor, Goldberg and Rosen, eds., BirkhauserVerlag-Basel, 67-79 (1993). The biological effect of HGF/SF may dependin part on the target cell. HGF induces a spectrum of biologicalactivities in epithelial cells, including mitogenesis, stimulation ofcell motility and promotion of matrix invasion (Biochem. Biophys. Res.Comm., 122:1450-1459 (1984); Proc. Natl. Acad. Sci. U.S.A., 88:415-419(1991)). It stimulates the motility and invasiveness of carcinoma cells,the former having been implicated in the migration of cells required formetastasis. HGF can also act as a “scatter factor”, an activity thatpromotes the dissociation of epithelial and vascular endothelial cells(Nature, 327:239-242 (1987); J. Cell Biol., 111:2097-2108 (1990); EMBOJ., 10:2867-2878 (1991); Proc. Natl. Acad. Sci. USA, 90:649-653 (1993)).Therefore, HGF is thought to be important in tumor invasion (HepatocyteGrowth Factor-Scatter Factor (HGF-SF) and the C-Met Receptor, Goldbergand Rosen, eds., Birkhauser Verlag-Basel, 131-165 (1993)).

HGF and c-Met are expressed at abnormally high levels in a large varietyof solid tumors. High levels of HGF and/or c-Met have been observed inliver, breast, pancreas, lung, kidney, bladder, ovary, brain, prostate,gallbladder and myeloma tumors in addition to many others. The role ofHGF/c-Met in metastasis has been investigated in mice using cell linestransformed with HGF/c-Met (J. Mol. Med., 74:505-513 (1996)).Qverexpression of the c-Met oncogene has also been suggested to play arole in the pathogenesis and progression of thyroid tumors derived fromfollicular epithelium (Oncogene, 7:2549-2553 (1992)). HGF is a morphogen(Development, 110:1271-1284 (1990); Cell, 66:697-711 (1991)) and apotent angiogenic factor (J. Cell Biol., 119:629-641 (1992)).

Recent work on the relationship between inhibition of angiogenesis andthe suppression or reversion of tumor progression shows great promise inthe treatment of cancer (Nature, 390:404-407 (1997)), especially the useof multiple angiogenesis inhibitors compared to the effect of a singleinhibitor. Angiogenesis can be stimulated by HGF, as well as vascularendothelial growth factor (VEGF) and basic fibroblast growth factor(bFGF).

Angiogenesis, the process of sprouting new blood vessels from existingvasculature and arteriogenesis, the remodeling of small vessels intolarger conduit vessels are both physiologically important aspects ofvascular growth in adult tissues. These processes of vascular growth arerequired for beneficial processes such as tissue repair, wound healing,recovery from tissue ischemia and menstrual cycling. They are alsorequired for the development of pathological conditions such as thegrowth of neoplasias, diabetic retinopathy, rheumatoid arthritis,psoriasis, certain forms of macular degeneration, and certaininflammatory pathologies. The inhibition of vascular growth in thesecontexts has also shown beneficial effects in preclinical animal models.For example, inhibition of angiogenesis by blocking vascular endothelialgrowth factor or its receptor has resulted in inhibition of tumor growthand in retinopathy. Also, the development of pathological pannus tissuein rheumatoid arthritis involves angiogenesis and might be blocked byinhibitors of angiogenesis.

The ability to stimulate vascular growth has potential utility fortreatment of ischemia-induced pathologies such as myocardial infarction,coronary artery disease, peripheral vascular disease, and stroke. Thesprouting of new vessels and/or the expansion of small vessels inischemic tissues prevents ischemic tissue death and induces tissuerepair. Certain diseases are known to be associated with deregulatedangiogenesis, for example ocular neovascularization, such asretinopathies (including diabetic retinopathy), age-related maculardegeneration, psoriasis, hemangioblastoma, hemangioma, arteriosclerosis,inflammatory disease, such as a rheumatoid or rheumatic inflammatorydisease, especially arthritis (including rheumatoid arthritis), or otherchronic inflammatory disorders, such as chronic asthma, arterial orpost-transplantational atherosclerosis, endometriosis, and neoplasticdiseases, for example so-called solid tumors and liquid tumors (such asleukemias). Treatment of malaria and related viral diseases may also bemediated by HGF and cMet.

Elevated levels of HGF and c-Met have also been observed innon-oncological settings, such as hypertension, myocardial infarctionand rheumatoid arthritis. It has been observed that levels of HGFincrease in the plasma of patients with hepatic failure (Gohda et al.,supra) and in the plasma (Hepatol., 13:734-750 (1991)) or serum (J.Biochem., 109:8-13 (1991)) of animals with experimentally induced liverdamage. HGF has also been shown to be a mitogen for certain cell types,including melanocytes, renal tubular cells, keratinocytes, certainendothelial cells and cells of epithelial origin (Biochem. Biophys. Res.Commun., 176:45-51 (1991); Biochem. Biophys. Res. Commun., 174:831-838(1991); Biochem., 30:9768-9780 (1991); Proc. Natl. Acad. Sci. USA,88:415-419 (1991)). Both HGF and the c-Met proto-oncogene have beenpostulated to play a role in microglial reactions to CNS injuries(Oncogene, 8:219-222 (1993)). Metastatic SCC cells overexpress c-Met andhave enhanced tumoregenesis and metastasis in vivo [G. Gong et al.,Oncogene, 23:6199-6208 (2004)]. C-Met is required for tumor cellsurvival [N. Shinomiya et al., Cancer Research, 64:7962-7970 (2004)].For a general review see C. Birchmeier et al., Nature Reviews/MolecularBiology 4:915-925 (2003).

In view of the role of HGF and/or c-Met in potentiating or promotingsuch diseases or pathological conditions, it would be useful to have ameans of substantially reducing or inhibiting one or more of thebiological effects of HGF and its receptor. Thus a compound that reducesthe effect of HGF would be a useful compound. Compounds of the currentinvention have not been previously described as inhibitors ofangiogenesis such as for the treatment of cancer.

Sugen application WO 05/010005 describes certain Triazolotriazinecompounds that are c-met inhibitors. Diamon Shamrock Corp. applicationWO 83/00864 discloses certain Triazolotriazine compounds that are usefulas anti-inflammatory agents. Yamanouchi applications EP 1481955 and US2005/0261297 disclose certain nitrogen-containing heterocyclic compoundsthat are therapeutic agents having a bone formation-stimulating effect.

Compounds of the current invention are inhibitors of c-Met.

DESCRIPTION OF THE INVENTION

A class of compounds useful in treating cancer and angiogenesis isdefined by Formulae I, II, III, IV, V, VI and VII

enantiomers, diastereomers, salts and solvates thereof wherein

-   J is N or CR³;-   W is N or CR^(2b);-   W* is N or CR^(2b);-   X is O or S;-   Z and Z* are independently —O—, —S(O)_(v)—, or —NR⁵—;-   R^(a), R^(b), R^(c) and R^(d) are each independently H, halo, alkyl,    alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, heterocyclo,    aryl, heteroaryl, —NO₂, —CN, —NR⁵R^(5a), —OR⁴, —C(═O)R⁴, —C(═O)OR⁴;    —C(═O)NR⁵R^(5a), —N(R⁵)C(═O)NR⁵R^(5a), —OC(═O)NR⁵R^(5a),    —S(O)_(v)R⁴, —S(O)₂NR⁵R^(5a), —N(R⁵)SO₂R⁴ any of which may be    optionally independently substituted with one or more R¹⁰ groups as    allowed by valance;-   or R^(a) and R^(b) together with the carbon atom to which they are    bonded may combine to form a 3-10 membered cycloalkyl, a 3-10    membered cycloalkenyl ring, or a heterocyclo ring, any of which may    be optionally substituted with one or more R¹⁰ groups as allowed by    valance;-   or R^(c) and R^(d) together with the carbon atom to which they are    bonded may combine to form a 3-10 membered cycloalkyl, a 3-10    membered cycloalkenyl ring, or a heterocyclo ring, any of which may    be optionally substituted with one or more R¹⁰ groups as allowed by    valance;-   or R^(a) and/or R^(b) may combine with any R^(c) or R^(d) to form a    partially or fully saturated 3-8 membered cycloalkyl ring or    heterocyclo ring, either of which may be optionally substituted with    one or more R¹⁰ groups as allowed by valance;-   or R^(a) and R^(b) may combine to form a carbonyl group;-   or R^(c) and R^(d) attached to the same carbon atom may combine to    form a carbonyl group;-   R¹ is aryl, heteroaryl or heterocyclo any of which may be optionally    independently substituted with one or more R¹⁰ groups as allowed by    valance;-   R² is    -   (i) H, halo, cyano, nitro, or;    -   (ii) alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl,        cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl,        heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, —OR⁴,        —S(O)_(v)R⁴, —NR⁵R^(5a), —C(═O)R⁴, —C(═S)R⁴, —C(═O)OR⁴,        —C(═S)OR⁴, —C(═O)NR⁵R^(5a), C(═S)NR⁵R^(5a), N(R⁵)C(═O)NR⁵R^(5a),        —N(R⁵)C(═S)NR⁵R^(5a), —N(R⁵)C(═O)R⁴, —N(R⁵)C(═S)R⁴,        —OC(═O)NR⁵R^(5a), —OC(═S)NR⁵R^(5a), —SO₂NR⁵R^(5a), —N(R⁵)SO₂R⁴,        —N(R⁵)SO₂NR⁵R^(5a), —N(R⁵)C(═O)OR⁴, —N(R⁵)C(═S)OR⁴, —N(R⁵)SO₂R⁴,        any of which may be optionally independently substituted with        one or more R¹⁰ as allowed by valance,-   provided that in compounds of formula I when W and J are both N, R²    is other than    -   (a) —NR⁵R^(5a) where R⁵ and R^(5a) are independently H, alkyl,        haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl,        heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, and        cycloalkylalkyl; and    -   (b) phenyl substituted with a group

-   -    where G¹ and G² are independently alkyl, cycloalkyl, or G¹ and        G² together with the nitrogen atom to which they are attached        combine to form a 5- to 8-membered heterocyclo ring;

-   R^(2a), R^(2b) and R³ are independently selected at each occurrence    from H, halo, cyano, nitro, alkyl, haloalkyl, alkenyl, alkynyl,    cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl,    heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, —OR⁴,    —S(O)_(v)R⁴, —NR⁵R^(5a), —C(═O)R⁴, —C(═S)R⁴, —C(═O)OR⁴, —C(═S)OR⁴,    —C(═O)NR⁵R^(5a), —C(═S)NR⁵R^(5a), —N(R⁵)C(═O)NR⁵R^(5a),    —N(R⁵)C(═S)NR⁵R^(5a), —N(R⁵)C(═O)R⁴, —N(R⁵)C(═S)R⁴,    —OC(═O)NR⁵R^(5a), —OC(═S)NR⁵R^(5a), —SO₂NR⁵R^(5a), —N(R⁵)SO₂R⁴,    —N(R⁵)SO₂NR⁵R^(5a), —N(R⁵)C(═O)OR⁴, —N(R⁵)C(═S)OR⁴, —N(R⁵)SO₂R⁴, any    of which may be optionally independently substituted with one or    more R¹⁰ groups as allowed by valance;

-   R⁴ is independently selected at each occurrence from H, alkyl,    haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl,    heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, and    cycloalkylalkyl, any of which may be optionally independently    substituted as allowed by valance with one or more R¹⁰ groups;

-   R⁵ and R^(5a) are independently selected at each occurrence from H,    alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl,    heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, and    cycloalkylalkyl, any of which may be optionally substituted as    allowed by valance with one or more R¹⁰; or R⁵ and R^(5a) may    combine to form a heterocyclo ring optionally substituted with one    or more R¹⁰;

-   R¹⁰ at each occurrence is independently, halo, cyano, nitro, oxo,    alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,    heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl,    cycloalkylalkyl, heterocycloalkyl, -(alkylene)_(m)-OR⁴,    -(alkylene)_(m)-S(O)_(m)R⁴, -(alkylene)_(m)-NR⁵R^(5a),    -(alkylene)_(m)-C(═O)R⁴, -(alkylene)_(m)-C(═S)R⁴,    -(alkylene)_(m)-C(═O)OR⁴, -(alkylene)_(m)-OC(═O)R⁴,    -(alkylene)_(m)-C(═S)OR⁴, -(alkylene)_(m)-C(═O)NR⁵R^(5a),    -(alkylene)_(m)-C(═S)NR⁵R^(5a), -(alkylene)_(m)-N(R⁵)C(═O)R⁴,    -(alkylene)_(m)-N(R⁵)C(═S)R⁴, -(alkylene)_(m)-OC(═O)NR⁵R^(5a),    -(alkylene)_(m)-OC(═S)NR⁵R^(5a), -(alkylene)_(m)-SO₂NR⁵R^(5a),    -(alkylene)_(m)-N(R⁵)SO₂R⁴, -(alkylene)_(m)-N(R⁵)SO₂NR⁵R^(5a),    -(alkylene)_(m)-N(R⁵)C(═O)OR⁴, -(alkylene)_(m)-N(R⁵)C(═S)OR⁴, or    -(alkylene)_(m)-N(R⁵)SO₂R⁴;

-   wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl,    heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be    further independently substituted with one or more    -(alkylene)_(m)-OR⁴, -(alkylene)_(m)-S(O)_(v)R⁴,    -(alkylene)_(m)-NR⁵R^(5a), -(alkylene)_(m)-C(═O)R⁴,    -(alkylene)_(m)-C(═S)R⁴, -(alkylene)_(m)-C(═O)OR⁴,    -(alkylene)_(m)-OC(═O)R⁴, -(alkylene)_(m)-C(═S)OR⁴,    -(alkylene)_(m)-C(═O)NR⁵R^(5a), -(alkylene)_(m)-C(═S)NR⁵R^(5a),    -(alkylene)_(m)-N(R⁵)C(═O)NR⁵R^(5a),    -(alkylene)_(m)-N(R⁵)C(═S)NR⁵R^(5a), -(alkylene)_(m)-N(R⁵)C(═O)R⁴,    -(alkylene)_(m)-N(R⁵)C(═S)R⁴, -(alkylene)_(m)-OC(═O)NR⁵R^(5a),    -(alkylene)_(m)-OC(═S)NR⁵R^(5a)-(alkylene)_(m)-SO₂NR⁵R^(5a),    -(alkylene)_(m)-N(R⁵)SO₂R⁴,    -(alkylene)_(m)-N(R⁵)SO₂NR⁵R^(5a)-(alkylene)_(m)-N(R⁵)C(═O)OR⁴,    -(alkylene)_(m)-N(R⁵)C(═S)OR⁴, or -(alkylene)_(m)-N(R⁵)SO₂R⁴;

-   and further wherein any two R¹⁰ groups attached to the same atom or    attached to adjacent atoms may combine to form an optionally    substituted 3- to 8 membered ring system;

-   m is 0 or 1;

-   n is 0, 1 or 2;

-   q and t are each independently 0 or 1;

-   v is 0, 1 or 2.

Preferred compounds include compounds wherein R¹ is phenyl, naphthyl,benzodioxolyl, benzooxazolyl, benzoisoxazolyl, pyridinyl, pyrimidinyl,pyrazinyl, pyrimidinyl, pyrazidinyl, isoquinolinyl, quinolinyl,quinazolinyl, quinazolinonyl, quinoxalinyl, naphthyridinyl,benzotriazinyl, triazolopyridinyl, triazolopyrimidinyl,triazolopyridazinyl, imidazopyridinyl, imidazopyrimidinyl,imidazopyridazinyl, pyrrolopyridinyl, pyrrolopyrimidinyl,pyrrolopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl,pyrazolopyridazinyl, cinnolinyl, thienopyridinyl, thienopyrimidinyl,thienopyridazinyl, furopyridinyl, furopyrimidinyl, furopyrazidinyl,benzofuranyl, benzoimidazolyl, indolyl, benzoisoxazolyl, benzothiazolyl,or benzoisothiazolyl any of which may be optionally independentlysubstituted with one or more R¹⁰ groups as allowed by valance.

Preferred R¹ groups include

where m* is 0, 1, 2, 3, 4, 5 or 6, as allowed by valence.

Especially preferred R¹ groups include

where R^(10a), R^(10b), R^(10y) and R^(10z) are independently absent,halo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl,-(alkylene)_(m)-OR⁴, -(alkylene)_(m)-NR⁵R^(5a), -(alkylene)_(m)-C(═O)R⁴,-(alkylene)_(m)-C(═O)OR⁴, -(alkylene)_(m)-OC(═O)R⁴,-(alkylene)_(m)-C(═O)NR⁵R^(5a), -(alkylene)_(m)-N(R⁵)C(═O)NR⁵R^(5a),-(alkylene)_(m)-N(R⁵)C(═O)R⁴, -(alkylene)_(m)-OC(═O)NR⁵R^(5a), or-(alkylene)_(m)-N(R⁵)C(═O)OR⁴;

or where R^(10a) and R^(10b) combine to form an optionally substituted3- to 8-membered ring system.

Most preferred R¹ groups include moieties that are either unsubstitutedor independently substituted as allowed by valance with one or morehalo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl,-(alkylene)_(m)-OR⁴, -(alkylene)_(m)-NR⁵R^(5a), -(alkylene)_(m)-C(═O)R⁴,-(alkylene)_(m)-C(═O)OR⁴, -(alkylene)_(m)-OC(═O)R⁴,-(alkylene)_(m)-C(═O)NR⁵R^(5a), -(alkylene)_(m)-N(R⁵)C(═O)NR⁵R^(5a),-(alkylene)_(m)-N(R⁵)C(═O)R⁴, -(alkylene)_(m)-OC(═O)NR⁵R^(5a), or-(alkylene)_(m)-N(R⁵)C(═O)OR⁴.

Preferred compounds of the present invention further include compoundswherein R² is H, halo, cyano, alkynyl, —C(═O)NR⁵R^(5a), —N(R⁵)C(═O)R⁴,—N(R⁵)C(═O)OR⁴, phenyl, naphthyl, pyrrolyl, imidazolyl, pyrazolyl,triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, pyridinyl, tetrahydropyridinyl, pyridinonyl,pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indolinyl,indolinonyl, isoidolinyl, isoindolinonyl, dihydrobenzofuranyl,dihydroisobenzofuranyl, benzofuranyl, isobenzofuranyl, quinolinyl,isoquinolinyl, quinazolinyl, quinazolinonyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl,quinoxalinyl, tetrahydroquinoxalinyl, benzomorpholinyl,dihydrobenzodioxinyl, imidazopyridinyl, naphthyridinyl, benzotriazinyl,triazolopyridinyl, triazolopyrimidinyl, triazolopyridazinyl,imidazopyridinyl, imidazopyrimidinyl, imidazopyridazinyl,pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl,pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, cinnolinyl,thienopyrrolyl, tetrahydrothienopyrrolyl, dihydrothienopyrrolonyl,thienopyridinyl, thienopyrimidinyl, thienopyridazinyl, furopyridinyl,furopyrimidinyl, furopyrazidinyl, benzofuranyl, benzoimidazolyl,benzoisoxazolyl, benzothiazolyl, or benzoisothiazolyl any of which maybe optionally independently substituted with one or more R¹⁰ groups asallowed by valance.

Preferred R² groups include

-   -   (a) halo, alkynyl, —C(═O)NR⁵R^(5a), —N(R⁵)C(═O)R⁴ or        —N(R⁵)C(═O)OR⁴ any of which may be optionally independently        substituted with one or more R¹⁰ groups as allowed by valance;        and    -   (b) an aryl, heteroaryl or heterocyclo ring system selected from

where m* is 0, 1, 2, 3, 4, 5 or 6, as allowed by valence.

Preferred compounds of the present invention include compounds havingeither or both of preferred R¹ groups and preferred R² groups eitheralone or in any combination thereof.

Preferred compounds of the present invention include compounds whereinR^(a), R^(b), R^(c) and R^(d) groups are independently hydrogen, alkyl(especially methyl), and halogen (especially fluorine).

Preferred compounds within the scope of formula I and II includecompounds of the following formualae IA, IB, IC, ID and IIA

enantiomers, diastereomers, salts and solvates thereof, whereinvariables R^(a), R^(b), R^(c), R^(d), R¹, R², R^(2a), R^(2b), R³, Z, Z*,n, q and t are as previously defined above. Preferred compounds offormulae IA, IB, IC, ID and IIA include compounds having any of thepreferred R¹ groups and R² groups, either alone or in any combinationthereof.

Preferred compounds within the scope of formula I and II also includecompounds having the following formula IE, IF, IIB and IIC

enantiomers, diastereomers, salts and solvates thereof wherein variablesR^(a), R^(b), R^(c), R^(d), R², R^(2a), R^(2b), and Z*, are aspreviously defined above, provided that in compounds of formula IE R² isnot phenyl substituted with a group

where G¹ and G² are independently alkyl, cycloalkyl, or G¹ and G²together with the nitrogen atom to which they are attached combine toform a 5- to 8-membered heterocyclo ring; and further wherein

-   q is 0, 1, 2 or 3;-   n* is 0, 1 or 2;-   t* is 0 or 1-   U¹, U², U³ and U⁴ are each independently C, or N; and-   R^(10c) at each occurrence is independently selected from the groups    listed in the definition of R¹⁰ previously described above.

Preferred compounds of formulae IE, IF, IIB and IIC include compoundshaving any of the preferred R² groups described above.

Preferred compounds within the scope of formulae IE and IF includecompounds of the following formula IEi, IEii, IEiii, IEiv, IFi, IFii,IFiii and IFiv

enantiomers, diastereomers, salts and solvates thereof.

Preferred compounds within the scope of formula I further includecompounds of the following formula IEA and IFA

enantiomers, diastereomers, salts and solvates thereof wherein variablesR^(a), R^(b), R^(c), R^(d), R², R^(2a), R^(2b), R^(1c), U¹, U², U³, Z*,n*, q, and t* are as previously defined above provided that in compoundsof formula IEA R² is not phenyl substituted with a group

where G¹ and G² are independently alkyl, cycloalkyl, or G¹ and G²together with the nitrogen atom to which they are attached combine toform a 5- to 8-membered heterocyclo ring. Preferred compounds offormulae IEA and IFA include compounds having any of the preferred R²groups described above.

Preferred compounds of formulae IEA and IFA include compounds offormulae IEAi, IEAii, IEAiii, IFAi, IFAii and IFAiii

enantiomers, diastereomers, salts and solvates thereof.

Preferred compounds within the scope of formula I further includecompounds of the following formula IG or IH

Wherein U is CR^(10c) or N, and variables R^(a), R^(b), R², R^(2a),R^(2b), R^(10a), R^(10b), R^(10c), and Z*, are as previously definedabove, provided that in compounds of formula IG R² is not phenylsubstituted with a group

where G¹ and G² are independently alkyl, cycloalkyl, or G¹ and G²together with the nitrogen atom to which they are attached combine toform a 5- to 8-membered heterocyclo ring. Preferred compounds offormulae IG and IH include compounds having any of the preferred R²groups described above.

Preferred compounds of the present invention include the compoundsexemplified herein.

The invention also relates to pharmaceutical compositions containing theabove compounds, together with a pharmaceutically acceptable vehicle orcarrier.

The invention also relates to a method of treating cancer in a subjectusing the above compounds.

The invention also relates to a method of reducing tumor size in asubject using the above compounds.

The invention also relates to a method of reducing metastasis in a tumorin a subject, using the above compounds.

The invention also relates to a method of treating HGF-mediateddisorders in a subject using the above compounds.

Indications

Compounds of the present invention would be useful for, but not limitedto, the prevention or treatment of angiogenesis related diseases. Thecompounds of the invention have c-Met inhibitory activity. The compoundsof the invention are useful in therapy as antineoplasia agents or tominimize deleterious effects of HGF.

Compounds of the invention would be useful for the treatment ofneoplasia including cancer and metastasis, including, but not limitedto: carcinoma such as cancer of the bladder, breast, colon, kidney,liver, lung (including small cell lung cancer), esophagus, gall-bladder,ovary, pancreas, stomach, cervix, thyroid, prostate, and skin (includingsquamous cell carcinoma); hematopoietic tumors of lymphoid lineage(including leukemia, acute lymphocitic leukemia, acute lymphoblasticleukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma,non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma);hematopoietic tumors of myeloid lineage (including acute and chronicmyelogenous leukemias, myelodysplastic syndrome and promyelocyticleukemia); tumors of mesenchymal origin (including fibrosarcoma andrhabdomyosarcoma, and other sarcomas, e.g. soft tissue and bone); tumorsof the central and peripheral nervous system (including astrocytoma,neuroblastoma, glioma and schwannomas); and other tumors (includingmelanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderomapigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi'ssarcoma).

Preferably, the compounds are useful for the treatment of neoplasiaselected from lung cancer, colon cancer and breast cancer.

The compounds also would be useful for treatment of opthalmologicalconditions such as corneal graft rejection, ocular neovascularization,retinal neovascularization including neovascularization following injuryor infection, diabetic retinopathy, retrolental fibroplasia andneovascular glaucoma; retinal ischemia; vitreous hemorrhage; ulcerativediseases such as gastric ulcer; pathological, but non-malignant,conditions such as hemangiomas, including infantile hemaginomas,angiofibroma of the nasopharynx and avascular necrosis of bone; anddisorders of the female reproductive system such as endometriosis. Thecompounds are also useful for the treatment of edema, and conditions ofvascular hyperpermeability.

The compounds of the invention are useful in therapy of proliferativediseases. These compounds can be used for the treatment of aninflammatory rheumatoid or rheumatic disease, especially ofmanifestations at the locomotor apparatus, such as various inflammatoryrheumatoid diseases, especially chronic polyarthritis includingrheumatoid arthritis, juvenile arthritis or psoriasis arthropathy;paraneoplastic syndrome or tumor-induced inflammatory diseases, turbideffusions, collagenosis, such as systemic Lupus erythematosus,poly-myositis, dermato-myositis, systemic sclerodermia or mixedcollagenosis; postinfectious arthritis (where no living pathogenicorganism can be found at or in the affected part of the body),seronegative spondylarthritis, such as spondylitis ankylosans;vasculitis, sarcoidosis, or arthrosis; or further any combinationsthereof. An example of an inflammation related disorder is (a) synovialinflammation, for example, synovitis, including any of the particularforms of synovitis, in particular bursal synovitis and purulentsynovitis, as far as it is not crystal-induced. Such synovialinflammation may for example, be consequential to or associated withdisease, e.g. arthritis, e.g. osteoarthritis, rheumatoid arthritis orarthritis deformans. The present invention is further applicable to thesystemic treatment of inflammation, e.g. inflammatory diseases orconditions, of the joints or locomotor apparatus in the region of thetendon insertions and tendon sheaths. Such inflammation may be, forexample, consequential to or associated with disease or further (in abroader sense of the invention) with surgical intervention, including,in particular conditions such as insertion endopathy, myofascialesyndrome and tendomyosis. The present invention is further especiallyapplicable to the treatment of inflammation, e.g. inflammatory diseaseor condition, of connective tissues including dermatomyositis andmyositis.

These compounds can be used as active agents against such disease statesas arthritis, atherosclerosis, psoriasis, hemangiomas, myocardialangiogenesis, coronary and cerebral collaterals, ischemic limbangiogenesis, wound healing, peptic ulcer Helicobacter related diseases,fractures, cat scratch fever, rubeosis, neovascular glaucoma andretinopathies such as those associated with diabetic retinopathy ormacular degeneration. In addition, some of these compounds can be usedas active agents against solid tumors, malignant ascites, hematopoieticcancers and hyperproliferative disorders such as thyroid hyperplasia(especially Grave's disease), and cysts (such as hypervascularity ofovarian stroma, characteristic of polycystic ovarian syndrome(Stein-Leventhal syndrome)) since such diseases require a proliferationof blood vessel cells for growth and/or metastasis.

Further, some of these compounds can be used as active agents againstburns, chronic lung disease, stroke, polyps, anaphylaxis, chronic andallergic inflammation, ovarian hyperstimulation syndrome, braintumor-associated cerebral edema, high-altitude, trauma or hypoxiainduced cerebral or pulmonary edema, ocular and macular edema, ascites,and other diseases where vascular hyperpermeability, effusions,exudates, protein extravasation, or edema is a manifestation of thedisease. The compounds will also be useful in treating disorders inwhich protein extravasation leads to the deposition of fibrin andextracellular matrix, promoting stromal proliferation (e.g. fibrosis,cirrhosis and carpal tunnel syndrome).

The compounds of the present invention are also useful in the treatmentof ulcers including bacterial, fungal, Mooren ulcers and ulcerativecolitis.

The compounds of the present invention are also useful in the treatmentof conditions wherein undesired angiogenesis, edema, or stromaldeposition occurs in viral infections such as Herpes simplex, HerpesZoster, AIDS, Kaposi's sarcoma, protozoan infections and toxoplasmosis,following trauma, radiation, stroke, endometriosis, ovarianhyperstimulation syndrome, systemic lupus, sarcoidosis, synovitis,Crohn's disease, sickle cell anemia, Lyme disease, pemphigoid, Paget'sdisease, hyperviscosity syndrome, Osler-Weber-Rendu disease, chronicinflammation, chronic occlusive pulmonary disease, asthma, andinflammatory rheumatoid or rheumatic disease. The compounds are alsouseful in the reduction of subcutaneous fat and for the treatment ofobesity.

The compounds of the present invention are also useful in the treatmentof ocular conditions such as ocular and macular edema, ocularneovascular disease, scleritis, radial keratotomy, uveitis, vitritis,myopia, optic pits, chronic retinal detachment, post-lasercomplications, glaucoma, conjunctivitis, Stargardt's disease and Ealesdisease in addition to retinopathy and macular degeneration.

The compounds of the present invention are also useful in the treatmentof cardiovascular conditions such as atherosclerosis, restenosis,arteriosclerosis, vascular occlusion and carotid obstructive disease.

The compounds of the present invention are also useful in the treatmentof cancer related indications such as solid tumors, sarcomas (especiallyEwing's sarcoma and osteosarcoma), retinoblastoma, rhabdomyosarcomas,neuroblastoma, hematopoietic malignancies, including leukemia andlymphoma, tumor-induced pleural or pericardial effusions, and malignantascites.

The compounds of the present invention are also useful in the treatmentof diabetic conditions such as diabetic retinopathy and microangiopathy.

The compounds of the present invention are also useful in the reductionof blood flow in a tumor in a subject.

The compounds of the present invention are also useful in the reductionof metastasis of a tumor in a subject.

The compounds of this invention may also act as inhibitors of otherprotein kinases, e.g. tie-2, lck, src, fgf, c-Met, ron, ckit and ret,and thus be effective in the treatment of diseases associated with otherprotein kinases.

Besides being useful for human treatment, these compounds are alsouseful for veterinary treatment of companion animals, exotic animals andfarm animals, including mammals, rodents, and the like. More preferredanimals include horses, dogs, and cats.

As used herein, the compounds of the present invention include thepharmaceutically acceptable derivatives thereof.

Where the plural form is used for compounds, salts, and the like, thisis taken to mean also a single compound, salt and the like.

Definitions

“Angiogenesis” is defined as any alteration of an existing vascular bedor the formation of new vasculature, which benefits tissue perfusion.This includes the formation of new vessels by sprouting of endothelialcells from existing blood vessels or the remodeling of existing vesselsto alter size, maturity, direction or flow properties to improve bloodperfusion of tissue.

As used herein, “HGF” refers to hepatocyte growth factor/scatter factor.This includes purified hepatocyte growth factor/scatter factor,fragments of hepatocyte growth factor/scatter factor, chemicallysynthesized fragments of hepatocyte growth factor/scatter factor,derivatives or mutated versions of hepatocyte growth factor/scatterfactor, and fusion proteins comprising hepatocyte growth factor/scatterfactor and another protein. “HGF” as used herein also includeshepatocyte growth factor/scatter factor isolated from species other thanhumans.

As used herein “c-Met” refers to the receptor for HGF. This includespurified receptor, fragments of receptor, chemically synthesizedfragments of receptor, derivatives or mutated versions of receptor, andfusion proteins comprising the receptor and another-protein. “c-Met” asused herein also includes the HGF receptor isolated from a species otherthan humans.

As used herein, “HGF” refers to hepatocyte growth factor/scatter factor.This includes purified hepatocyte growth factor/scatter factor,fragments of hepatocyte growth factor/scatter factor, chemicallysynthesized fragments of hepatocyte growth factor/scatter factor,derivatives or mutated versions of hepatocyte growth factor/scatterfactor, and fusion proteins comprising hepatocyte growth factor/scatterfactor and another protein. “HGF” as used herein also includeshepatocyte growth factor/scatter factor isolated from species other thanhumans.

As used herein “c-Met” refers to the receptor for HGF. This includespurified receptor, fragments of receptor, chemically synthesizedfragments of receptor, derivatives or mutated versions of receptor, andfusion proteins comprising the receptor and another protein. “c-Met” asused herein also includes the HGF receptor isolated from a species otherthan humans.

As used herein, the terms “hepatocyte growth factor” and “HGF” refer toa growth factor typically having a structure with six domains (finger,Kringle 1, Kringle 2, Kringle 3, Kringle 4 and serine protease domains).Fragments of HGF constitute HGF with fewer domains and variants of HGFmay have some of the domains of HGF repeated; both are included if theystill retain their respective ability to bind a HGF receptor. The terms“hepatocyte growth factor” and “HGF” include hepatocyte growth factorfrom humans (“huHGF”) and any non-human mammalian species, and inparticular rat HGF. The terms as used herein include mature, pre,pre-pro, and pro forms, purified from a natural source, chemicallysynthesized or recombinantly produced. Human HGF is encoded by the cDNAsequence published by Miyazawa et al. (1989), supra, or Nakamura et al.(1989), supra. The sequences reported by Miyazawa et al. and Nakamura etal. differ in 14 amino acids. The reason for the differences is notentirely clear; polymorphism or cloning artifacts are among thepossibilities. Both sequences are specifically encompassed by theforegoing terms. It will be understood that natural allelic variationsexist and can occur among individuals, as demonstrated by one or moreamino acid differences in the amino acid sequence of each individual.The terms “hepatocyte growth factor” and “HGF” specifically include thedelta 5 huHGF as disclosed by Seki et al., supra.

The terms “HGF receptor” and “c-Met” when used herein refer to acellular receptor for HGF, which typically-includes an extracellulardomain, a transmembrane domain and an intracellular domain, as well asvariants and fragments thereof which retain the ability to bind HGF. Theterms “HGF receptor” and “c-Met” include the polypeptide molecule thatcomprises the full-length, native amino acid sequence encoded by thegene variously known as p190.sup.MET. The present definitionspecifically encompasses soluble forms of HGF receptor, and HGF receptorfrom natural sources, synthetically produced in vitro or obtained bygenetic manipulation including methods of recombinant DNA technology.The HGF receptor variants or fragments preferably share at least about65% sequence homology, and more preferably at least about 75% sequencehomology with any domain of the human c-Met amino acid sequencepublished in Rodrigues et al., Mol. Cell. Biol., 11:2962-2970 (1991);Park et al., Proc. Natl. Acad. Sci., 84:6379-6383 (1987); or Ponzetto etal., Oncogene, 6:553-559 (1991).

The terms “agonist” and “agonistic” when used herein refer to ordescribe a molecule which is capable of, directly or indirectly,substantially inducing, promoting or enhancing HGF biological activityor HGF receptor activation.

The terms “cancer” and “cancerous” when used herein refer to or describethe physiological condition in mammals that is typically characterizedby unregulated cell growth. Examples of cancer include but are notlimited to, carcinoma, lymphoma, sarcoma, blastoma and leukemia. Moreparticular examples of such cancers include squamous cell carcinoma,lung cancer, pancreatic cancer, cervical cancer, bladder cancer,hepatoma, breast cancer, colon carcinoma, and head and neck cancer.While the term “cancer” as used herein is not limited to any onespecific form of the disease, it is believed that the methods of theinvention will be particularly effective for cancers which are found tobe accompanied by increased levels of HGF or expression of c-Met in themammal.

The terms “treating,” “treatment,” and “therapy” as used herein refer tocurative therapy, prophylactic therapy, and preventative therapy.

The term “mammal” as used herein refers to any mammal classified as amammal, including humans, cows, horses, dogs and cats. In a preferredembodiment of the invention, the mammal is a human.

Given that elevated levels of c-Met and HGF are observed inhypertension, arteriosclerosis, myocardial infarction, and rheumatoidarthritis, nucleic acid ligands will serve as useful therapeutic agentsfor these diseases.

The term “treatment” includes therapeutic treatment as well asprophylactic treatment (either preventing the onset of disordersaltogether or delaying the onset of a pre-clinically evident stage ofdisorders in individuals).

A “pharmaceutically-acceptable derivative” denotes any salt, ester of acompound of this invention, or any other compound which uponadministration to a patient is capable of providing (directly orindirectly) a compound of this invention, or a metabolite or residuethereof, characterized by the ability to inhibit angiogenesis.

The phrase “therapeutically-effective” is intended to qualify the amountof each agent, which will achieve the goal of improvement in disorderseverity and the frequency of incidence over treatment of each agent byitself, while avoiding adverse side effects typically associated withalternative therapies. For example, effective neoplastic therapeuticagents prolong the survivability of the patient, inhibit the rapidlyproliferating cell growth associated with the neoplasm, or effect aregression of the neoplasm.

The term “H” denotes a single hydrogen atom. This radical may beattached, for example, to an oxygen atom to form a hydroxyl radical.

Where the term “alkyl” is used, either alone or within other terms suchas “haloalkyl” and “alkylamino”, it embraces linear or branched radicalshaving one to about twelve carbon atoms. More preferred alkyl radicalsare “lower alkyl” radicals having one to about six carbon atoms.Examples of such radicals include methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl and thelike. Even more preferred are lower alkyl radicals having one or twocarbon atoms. The term “alkylenyl” embraces bridging divalent alkylradicals such as methylenyl and ethylenyl. The term “lower alkylsubstituted with R²” does not include an acetal moiety.

The term “alkenyl” embraces linear or branched radicals having at leastone carbon-carbon double bond of two to about twelve carbon atoms. Morepreferred alkenyl radicals are “lower alkenyl” radicals having two toabout six carbon atoms. Most preferred lower alkenyl radicals areradicals having two to about four carbon atoms. Examples of alkenylradicals include ethenyl, propenyl, allyl, propenyl, butenyl and4-methylbutenyl. The terms “alkenyl” and “lower alkenyl”, embraceradicals having “cis” and “trans” orientations, or alternatively, “E”and “Z” orientations.

The term “alkynyl” denotes linear or branched radicals having at leastone carbon-carbon triple bond and having two to about twelve carbonatoms. More preferred alkynyl radicals are “lower alkynyl” radicalshaving two to about six carbon atoms. Most preferred are lower alkynylradicals having two to about four carbon atoms. Examples of suchradicals include propargyl, butynyl, and the like.

Alkyl, alkylenyl, alkenyl, and alkynyl radicals may be optionallysubstituted with one or more functional groups such as halo, hydroxy,nitro, amino, cyano, haloalkyl, aryl, heteroaryl, heterocyclo and thelike.

The term “halo” means halogens such as fluorine, chlorine, bromine oriodine atoms.

The term “haloalkyl” embraces radicals wherein any one or more of thealkyl carbon atoms is substituted with halo as defined above.Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkylradicals including perhaloalkyl. A monohaloalkyl radical, for oneexample, may have either an iodo, bromo, chloro or fluoro atom withinthe radical. Dihalo and polyhaloalkyl radicals may have two or more ofthe same halo atoms or a combination of different halo radicals. “Lowerhaloalkyl” embraces radicals having 1-6 carbon atoms. Even morepreferred are lower haloalkyl radicals having one to three carbon atoms.Examples of haloalkyl radicals include fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl anddichloropropyl. “Perfluoroalkyl” means alkyl radicals having allhydrogen atoms replaced with fluoro atoms. Examples includetrifluoromethyl and pentafluoroethyl.

The term “hydroxyalkyl” embraces linear or branched alkyl radicalshaving one to about ten carbon atoms any one of which may be substitutedwith one or more hydroxyl radicals. More preferred hydroxyalkyl radicalsare “lower hydroxyalkyl” radicals having one to six carbon atoms and oneor more hydroxyl radicals. Examples of such radicals includehydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl andhydroxyhexyl. Even more preferred are lower hydroxyalkyl radicals havingone to three carbon atoms.

The term “alkoxy” embraces linear or branched oxy-containing radicalseach having alkyl portions of one to about ten carbon atoms. Morepreferred alkoxy radicals are “lower alkoxy” radicals having one to sixcarbon atoms. Examples of such radicals include methoxy, ethoxy,propoxy, butoxy and tert-butoxy. Even more preferred are lower alkoxyradicals having one to three carbon atoms. Alkoxy radicals may befurther substituted with one or more halo atoms, such as fluoro, chloroor bromo, to provide “haloalkoxy” radicals. Even more preferred arelower haloalkoxy radicals having one to three carbon atoms. Examples ofsuch radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy,trifluoroethoxy, fluoroethoxy and fluoropropoxy.

The term “aryl”, alone or in combination, means a carbocyclic aromaticsystem containing one or two rings wherein such rings may be attachedtogether in a fused manner. The term “aryl” embraces aromatic radicalssuch as phenyl, naphthyl, indenyl, tetrahydronaphthyl, and indanyl. Morepreferred aryl is phenyl. Said “aryl” group may have 1 or moresubstituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro,cyano, alkoxy, lower alkylamino, and the like. Phenyl substituted with—O—CH₂—O— forms the aryl benzodioxolyl substituent.

The term “heterocyclyl” (or “heterocyclo”) embraces saturated, andpartially saturated and heteroatom-containing ring radicals, where theheteroatoms may be selected from nitrogen, sulfur and oxygen. It doesnot include rings containing —O—O—, —O—S— or —S—S— portions. Said“heterocyclyl” group may have 1 to 3 substituents such as hydroxyl, Boc,halo, haloalkyl, cyano, lower alkyl, lower aralkyl, oxo, lower alkoxy,amino, lower alkylamino, and the like.

Examples of saturated heterocyclic radicals include saturated 3 to6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms[e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl,piperazinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.morpholinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,thiazolidinyl]. Examples of partially saturated heterocyclyl radicalsinclude dihydrothienyl, dihydropyranyl, dihydrofuryl, dihydrothiazolyl,and the like.

Particular examples of partially saturated and saturated heterocyclylinclude pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl,pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl,thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl,indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl,isochromanyl, chromanyl, 1,2-dihydroquinolyl,1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl,2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl,2,3-dihydro-1H-λ′-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryland dihydrothiazolyl, and the like.

The term heterocyclyl, (or heterocyclo) also embraces radicals whereheterocyclic radicals are fused/condensed with aryl radicals:unsaturated condensed heterocyclic group containing 1 to 5 nitrogenatoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl,quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl[e.g., tetrazolo[1,5-b]pyridazinyl]; unsaturated condensed heterocyclicgroup containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.benzoxazolyl, benzoxadiazolyl]; unsaturated condensed heterocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,benzothiazolyl, benzothiadiazolyl]; and saturated, partially unsaturatedand unsaturated condensed heterocyclic group containing 1 to 2 oxygen orsulfur atoms [e.g. benzofuryl, benzothienyl,2,3-dihydro-benzo[1,4]dioxinyl and dihydrobenzofuryl].

The term “heteroaryl” denotes aryl ring systems that contain one or moreheteroatoms selected from the group O, N and S, wherein the ringnitrogen and sulfur atom(s) are optionally oxidized, and nitrogenatom(s) are optionally quarternized. Examples include unsaturated 5 to 6membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, forexample, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl,4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g.,4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl]; unsaturated5- to 6-membered heteromonocyclic group containing an oxygen atom, forexample, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-memberedheteromonocyclic group containing a sulfur atom, for example, 2-thienyl,3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example,oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated 5 to 6-memberedheteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g.,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl].

The term “sulfonyl”, whether used alone or linked to other terms such asalkylsulfonyl, denotes respectively divalent radicals —SO₂—.

The terms “sulfamyl,” “aminosulfonyl” and “sulfonamidyl,” denotes asulfonyl radical substituted with an amine radical, forming asulfonamide (—SO₂NH₂).

The term “alkylaminosulfonyl” includes “N-alkylaminosulfonyl” wheresulfamyl radicals are independently substituted with one or two alkylradical(s).

More preferred alkylaminosulfonyl radicals are “loweralkylaminosulfonyl” radicals having one to six carbon atoms. Even morepreferred are lower alkylaminosulfonyl radicals having one to threecarbon atoms. Examples of such lower alkylaminosulfonyl radicals includeN-methylaminosulfonyl, and N-ethylaminosulfonyl.

The terms “carboxy” or “carboxyl”, whether used alone or with otherterms, such as “carboxyalkyl”, denotes —CO₂H.

The term “carbonyl”, whether used alone or with other terms, such as“aminocarbonyl”, denotes —(C═O)—.

The term “aminocarbonyl” denotes an amide group of the formula—C(═O)NH₂.

The terms “N-alkylaminocarbonyl” and “N,N-dialkylaminocarbonyl” denoteaminocarbonyl radicals independently substituted with one or two alkylradicals, respectively. More preferred are “lower alkylaminocarbonyl”having lower alkyl radicals as described above attached to anaminocarbonyl radical.

The terms “N-arylaminocarbonyl” and “N-alkyl-N-arylaminocarbonyl” denoteaminocarbonyl radicals substituted, respectively, with one aryl radical,or one alkyl and one aryl radical.

The terms “heterocyclylalkylenyl” and “heterocyclylalkyl” embraceheterocyclic-substituted alkyl radicals. More preferredheterocyclylalkyl radicals are “5- or 6-membered heteroarylalkyl”radicals having alkyl portions of one to six carbon atoms and a 5- or6-membered heteroaryl radical. Even more preferred are lowerheteroarylalkylenyl radicals having alkyl portions of one to threecarbon atoms. Examples include such radicals as pyridylmethyl andthienylmethyl.

The term “aralkyl” embraces aryl-substituted alkyl radicals. Preferablearalkyl radicals are “lower aralkyl” radicals having aryl radicalsattached to alkyl radicals having one to six carbon atoms. Even morepreferred are “phenylalkylenyl” attached to alkyl portions having one tothree carbon atoms. Examples of such radicals include benzyl,diphenylmethyl and phenylethyl. The aryl in said aralkyl may beadditionally substituted with halo, alkyl, alkoxy, halkoalkyl andhaloalkoxy.

The term “alkylthio” embraces radicals containing a linear or branchedalkyl radical, of one to ten carbon atoms, attached to a divalent sulfuratom. Even more preferred are lower alkylthio radicals having one tothree carbon atoms. An example of “alkylthio” is methylthio, (CH₃S—).

The term “haloalkylthio” embraces radicals containing a haloalkylradical, of one to ten carbon atoms, attached to a divalent sulfur atom.Even more preferred are lower haloalkylthio radicals having one to threecarbon atoms. An example of “haloalkylthio” is trifluoromethylthio.

The term “alkylamino” embraces “N-alkylamino” and “N,N-dialkylamino”where amino groups are independently substituted with one alkyl radicaland with two alkyl radicals, respectively. More preferred alkylaminoradicals are “lower alkylamino” radicals having one or two alkylradicals of one to six carbon atoms, attached to a nitrogen atom. Evenmore preferred are lower alkylamino radicals having one to three carbonatoms. Suitable alkylamino radicals may be mono or dialkylamino such asN-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino and thelike.

The term “arylamino” denotes amino groups, which have been substitutedwith one or two aryl radicals, such as N-phenylamino. The arylaminoradicals may be further substituted on the aryl ring portion of theradical.

The term “heteroarylamino” denotes amino groups, which have beensubstituted with one or two heteroaryl radicals, such as N-thienylamino.The “heteroarylamino” radicals may be further substituted on theheteroaryl ring portion of the radical.

The term “aralkylamino” denotes amino groups, which have beensubstituted with one or two aralkyl radicals. More preferred arephenyl-C₁-C₃-alkylamino radicals, such as N-benzylamino. Thearalkylamino radicals may be further substituted on the aryl ringportion.

The terms “N-alkyl-N-arylamino” and “N-aralkyl-N-alkylamino” denoteamino groups, which have been independently substituted with one aralkyland one alkyl radical, or one aryl and one alkyl radical, respectively,to an amino group.

The term “aminoalkyl” embraces linear or branched alkyl radicals havingone to about ten carbon atoms any one of which may be substituted withone or more amino radicals. More preferred aminoalkyl radicals are“lower aminoalkyl” radicals having one to six carbon atoms and one ormore amino radicals.

Examples of such radicals include aminomethyl, aminoethyl, aminopropyl,aminobutyl and aminohexyl. Even more preferred are lower aminoalkylradicals having one to three carbon atoms.

The term “alkylaminoalkyl” embraces alkyl radicals substituted withalkylamino radicals. More preferred alkylaminoalkyl radicals are “loweralkylaminoalkyl” radicals having alkyl radicals of one to six carbonatoms. Even more preferred are lower alkylaminoalkyl radicals havingalkyl radicals of one to three carbon atoms. Suitable alkylaminoalkylradicals may be mono or dialkyl substituted, such asN-methylaminomethyl, N,N-dimethyl-aminoethyl, N,N-diethylaminomethyl andthe like.

The term “alkylaminoalkoxy” embraces alkoxy radicals substituted withalkylamino radicals. More preferred alkylaminoalkoxy radicals are “loweralkylaminoalkoxy” radicals having alkoxy radicals of one to six carbonatoms.

Even more preferred are lower alkylaminoalkoxy radicals having alkylradicals of one to three carbon atoms. Suitable alkylaminoalkoxyradicals may be mono or dialkyl substituted, such asN-methylaminoethoxy, N,N-dimethylaminoethoxy, N,N-diethylaminoethoxy andthe like.

The term “alkylaminoalkoxyalkoxy” embraces alkoxy radicals substitutedwith alkylaminoalkoxy radicals. More preferred alkylaminoalkoxyalkoxyradicals are “lower alkylaminoalkoxyalkoxy” radicals having alkoxyradicals of one to six carbon atoms. Even more preferred are loweralkylaminoalkoxyalkoxy radicals having alkyl radicals of one to threecarbon atoms. Suitable alkylaminoalkoxyalkoxy radicals may be mono ordialkyl substituted, such as N-methylaminomethoxyethoxy,N-methylaminoethoxyethoxy, N,N-dimethylaminoethoxyethoxy,N,N-diethylaminomethoxymethoxy and the like.

The term “carboxyalkyl” embraces linear or branched alkyl radicalshaving one to about ten carbon atoms any one of which may be substitutedwith one or more carboxy radicals. More preferred carboxyalkyl radicalsare “lower carboxyalkyl” radicals having one to six carbon atoms and onecarboxy radical. Examples of such radicals include carboxymethyl,carboxypropyl, and the like. Even more preferred are lower carboxyalkylradicals having one to three CH₂ groups.

The term “halosulfonyl” embraces sulfonyl radicals substituted with ahalogen radical. Examples of such halosulfonyl radicals includechlorosulfonyl and fluorosulfonyl.

The term “arylthio” embraces aryl radicals of six to ten carbon atoms,attached to a divalent sulfur atom. An example of “arylthio” isphenylthio.

The term “aralkylthio” embraces aralkyl radicals as described above,attached to a divalent sulfur atom. More preferred arephenyl-C₁-C₃-alkylthio radicals. An example of “aralkylthio” isbenzylthio.

The term “aryloxy” embraces optionally substituted aryl radicals, asdefined above, attached to an oxygen atom. Examples of such radicalsinclude phenoxy.

The term “aralkoxy” embraces oxy-containing aralkyl radicals attachedthrough an oxygen atom to other radicals. More preferred aralkoxyradicals are “lower aralkoxy” radicals having optionally substitutedphenyl radicals attached to lower alkoxy radical as described above.

The term “heteroaryloxy” embraces optionally substituted heteroarylradicals, as defined above, attached to an oxygen atom.

The term “heteroarylalkoxy” embraces oxy-containing heteroarylalkylradicals attached through an oxygen atom to other radicals. Morepreferred heteroarylalkoxy radicals are “lower heteroarylalkoxy”radicals having optionally substituted heteroaryl radicals attached tolower alkoxy radical as described above.

The term “cycloalkyl” includes saturated carbocyclic groups. Preferredcycloalkyl groups include C₃-C₆ rings. More preferred compounds include,cyclopentyl, cyclopropyl, and cyclohexyl.

The term “cycloalkylalkyl” embraces cycloalkyl-substituted alkylradicals. Preferable cycloalkylalkyl radicals are “lowercycloalkylalkyl” radicals having cycloalkyl radicals attached to alkylradicals having one to six carbon atoms. Even more preferred are“5-6-membered cycloalkylalkyl” attached to alkyl portions having one tothree carbon atoms. Examples of such radicals include cyclohexylmethyl.The cycloalkyl in said radicals may be additionally substituted withhalo, alkyl, alkoxy and hydroxy.

The term “cycloalkenyl” includes carbocyclic groups having one or morecarbon-carbon double bonds including “cycloalkyldienyl” compounds.Preferred cycloalkenyl groups include C₃-C₆ rings. More preferredcompounds include, for example, cyclopentenyl, cyclopentadienyl,cyclohexenyl and cycloheptadienyl.

The term “comprising” is meant to be open ended, including the indicatedcomponent but not excluding other elements.

The term(s) “Formulas I, II, III, IV, V, VI and VII” either alone or incombination includes any sub formulas.

The compounds of the invention are endowed with c-Met inhibitoryactivity.

The present invention also comprises the use of a compound of theinvention, or pharmaceutically acceptable salt thereof, in themanufacture of a medicament for the treatment either acutely orchronically of an angiogenesis mediated disease state, including thosedescribed previously. The compounds of the present invention are usefulin the manufacture of an anti-cancer medicament. The compounds of thepresent invention are also useful in the manufacture of a medicament toattenuate or prevent disorders through inhibition of c-Met.

The present invention comprises a pharmaceutical composition comprisinga therapeutically effective amount of a compound of the currentinvention in association with a least one pharmaceutically acceptablecarrier, adjuvant or diluent.

The present invention also comprises a method of treating angiogenesisrelated disorders in a subject having or susceptible to such disorder,the method comprising treating the subject with a therapeuticallyeffective amount of a compound of the current invention.

Combinations

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more compounds of the invention or other agents. Whenadministered as a combination, the therapeutic agents can be formulatedas separate compositions that are administered at the same time orsequentially at different times, or the therapeutic agents can be givenas a single composition.

The phrase “co-therapy” (or “combination-therapy”), in defining use of acompound of the present invention and another pharmaceutical agent, isintended to embrace administration of each agent in a sequential mannerin a regimen that will provide beneficial effects of the drugcombination, and is intended as well to embrace co-administration ofthese agents in a substantially simultaneous manner, such as in a singlecapsule having a fixed ratio of these active agents or in multiple,separate capsules for each agent.

Specifically, the administration of compounds of the present inventionmay be in conjunction with additional therapies known to those skilledin the art in the prevention or treatment of neoplasia, such as withradiation therapy or with cytostatic or cytotoxic agents.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the accepted dosage ranges. Compoundsof the current invention may also be administered sequentially withknown anticancer or cytotoxic agents when a combination formulation isinappropriate. The invention is not limited in the sequence ofadministration; compounds of the invention may be administered eitherprior to, simultaneous with or after administration of the knownanticancer or cytotoxic agent.

Currently, standard treatment of primary tumors consists of surgicalexcision followed by either radiation or IV administered chemotherapy.The typical chemotherapy regime consists of either DNA alkylatingagents, DNA intercalating agents, CDK inhibitors, or microtubulepoisons. The chemotherapy doses used are just below the maximaltolerated dose and therefore dose limiting toxicities typically include,nausea, vomiting, diarrhea, hair loss, neutropenia and the like.

There are large numbers of antineoplastic agents available in commercialuse, in clinical evaluation and in pre-clinical development, which wouldbe selected for treatment of neoplasia by combination drug chemotherapy.Such antineoplastic agents fall into several major categories, namely,antibiotic-type agents, alkylating agents, antimetabolite agents,hormonal agents, immunological agents, interferon-type agents and acategory of miscellaneous agents.

A first family of antineoplastic agents, which may be used incombination with compounds of the present invention, consists ofantimetabolite-type/thymidilate synthase inhibitor antineoplasticagents. Suitable antimetabolite antineoplastic agents may be selectedfrom but not limited to the group consisting of 5-FU-fibrinogen,acanthifolic acid, aminothiadiazole, brequinar sodium, carmofur,Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabine phosphatestearate, cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC,dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC,doxifluridine, Wellcome EHNA, Merck & Co. EX-015, fazarabine,floxuridine, fludarabine phosphate, 5-fluorouracil,N-(2′-furanidyl)-5-fluorouracil, Daiichi Seiyaku FO-152, isopropylpyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim,methotrexate, Wellcome MZPES, norspermidine, NCI NSC-127716, NCINSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA,pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, TakedaTAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, tyrosinekinase inhibitors, Taiho UFT and uricytin.

A second family of antineoplastic agents, which may be used incombination with compounds of the present invention, consists ofalkylating-type antineoplastic agents. Suitable alkylating-typeantineoplastic agents may be selected from but not limited to the groupconsisting of Shionogi 254-S, aldo-phosphamide analogues, altretamine,anaxirone, Boehringer Mannheim BBR-2207, bestrabucil, budotitane,Wakunaga CA-102, carboplatin, carmustine, Chinoin-139, Chinoin-153,chlorambucil, cisplatin, cyclophosphamide, American Cyanamid CL-286558,Sanofi CY-233, cyplatate, Degussa D-19-384, Sumimoto DACHP(Myr)₂,diphenylspiromustine, diplatinum cytostatic, Erba distamycinderivatives, Chugai DWA-2114R, ITI E09, elmustine, Erbamont FCE-24517,estramustine phosphate sodium, fotemustine, Unimed G-6-M, ChinoinGYKI-17230, hepsul-fam, ifosfamide, iproplatin, lomustine, mafosfamide,mitolactol, Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC-342215,oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-119, ranimustine,semustine, SmithKline SK&F-101772, Yakult Honsha SN-22, spiromus-tine,Tanabe Seiyaku TA-077, tauromustine, temozolomide, teroxirone,tetraplatin and trimelamol.

A third family of antineoplastic agents which may be used in combinationwith compounds of the present invention consists of antibiotic-typeantineoplastic agents. Suitable antibiotic-type antineoplastic agentsmay be selected from but not limited to the group consisting of Taiho4181-A, aclarubicin, actinomycin D, actinoplanone, Erbamont ADR-456,aeroplysinin derivative, Ajinomoto AN-201-II, Ajinomoto AN-3, NipponSoda anisomycins, anthracycline, azino-mycin-A, bisucaberin,Bristol-Myers BL-6859, Bristol-Myers BMY-25067, Bristol-Myers BMY-25551,Bristol-Myers BMY-26605, Bristol-Myers BMY-27557, Bristol-MyersBMY-28438, bleomycin sulfate, bryostatin-1, Taiho C-1027, calichemycin,chromoximycin, dactinomycin, daunorubicin, Kyowa Hakko DC-102, KyowaHakko DC-79, Kyowa Hakko DC-88A, Kyowa Hakko DC89-A1, Kyowa HakkoDC92-B, ditrisarubicin B, Shionogi DOB-41, doxorubicin,doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin, esorubicin,esperamicin-A1, esperamicin-Alb, Erbamont FCE-21954, Fujisawa FK-973,fostriecin, Fujisawa FR-900482, glidobactin, gregatin-A, grincamycin,herbimycin, idarubicin, illudins, kazusamycin, kesarirhodins, KyowaHakko KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko KT-5432, Kyowa HakkoKT-5594, Kyowa Hakko KT-6149, American Cyanamid LL-D49194, Meiji SeikaME 2303, menogaril, mitomycin, mitoxantrone, SmithKline M-TAG,neoenactin, Nippon Kayaku NK-313, Nippon Kayaku NKT-01, SRIInternational NSC-357704, oxalysine, oxaunomycin, peplomycin, pilatin,pirarubicin, porothramycin, pyrindanycin A, Tobishi RA-I, rapamycin,rhizoxin, rodorubicin, sibanomicin, siwenmycin, Sumitomo SM-5887, SnowBrand SN-706, Snow Brand SN-07, sorangicin-A, sparsomycin, SSPharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS PharmaceuticalSS-9816B, steffimycin B, Taiho 4181-2, talisomycin, Takeda TAN-868A,terpentecin, thrazine, tricrozarin A, Upjohn U-73975, Kyowa HakkoUCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024 and zorubicin.

A fourth family of antineoplastic agents which may be used incombination with compounds of the present invention consists of amiscellaneous family of antineoplastic agents, including tubulininteracting agents, topoisomerase II inhibitors, topoisomerase Iinhibitors and hormonal agents, selected from but not limited to thegroup consisting of α-carotene, α-difluoromethyl-arginine, acitretin,Biotec AD-5, Kyorin AHC-52, alstonine, amonafide, amphethinile,amsacrine, Angiostat, ankinomycin, anti-neoplaston A10, antineoplastonA2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, HenkelAPD, aphidicolin glycinate, asparaginase, Avarol, baccharin, batracylin,benfluoron, benzotript, Ipsen-Beaufour BIM-23015, bisantrene,Bristol-Myers BMY-40481, Vestar boron-10, bromofosfamide, WellcomeBW-502, Wellcome BW-773, caracemide, carmethizole hydrochloride,Ajinomoto CDAF, chlorsulfaquinoxalone, Chemes CHX-2053, Chemex CHX-100,Warner-Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941,Warner-Lambert CI-958, clanfenur, claviridenone, ICN compound 1259, ICNcompound 4711, Contracan, Yakult Honsha CPT-11, crisnatol, curaderm,cytochalasin B, cytarabine, cytocytin, Merz D-609, DABIS maleate,dacarbazine, datelliptinium, didemnin-B, dihaematoporphyrin ether,dihydrolenperone, dinaline, distamycin, Toyo Pharmar DM-341, ToyoPharmar DM-75, Daiichi Seiyaku DN-9693, docetaxel elliprabin,elliptinium acetate, Tsumura EPMTC, the epothilones, ergotamine,etoposide, etretinate, fenretinide, Fujisawa FR-57704, gallium nitrate,genkwadaphnin, Chugai GLA-43, Glaxo GR-63178, grifolan NMF-5N,hexadecylphosphocholine, Green Cross HO-221, homoharringtonine,hydroxyurea, BTG ICRF-187, ilmofosine, isoglutamine, isotretinoin,Otsuka JI-36, Ramot K-477, Otsuak K-76COONa, Kureha Chemical K-AM, MECTCorp KI-8110, American Cyanamid L-623, leukoregulin, lonidamine,Lundbeck LU-23-112, Lilly LY-186641, NCl (US) MAP, marycin, Merrel DowMDL-27048, Medco MEDR-340, merbarone, merocyanlne derivatives,methylanilinoacridine, Molecular Genetics MGI-136, minactivin,mitonafide, mitoquidone mopidamol, motretinide, Zenyaku Kogyo MST-16,N-(retinoyl)amino acids, Nisshin Flour Milling N-021,N-acylated-dehydroalanines, nafazatrom, Taisho NCU-190, nocodazolederivative, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782,NCI NSC-95580, ocreotide, Ono ONO-112, oquizanocine, Akzo Org-10172,paclitaxel, pancratistatin, pazelliptine, Warner-Lambert PD-111707,Warner-Lambert PD-115934, Warner-Lambert PD-131141, Pierre FabrePE-1001, ICRT peptide D, piroxantrone, polyhaematoporphyrin, polypreicacid, Efamol porphyrin, probimane, procarbazine, proglumide, Invitronprotease nexin I, Tobishi RA-700, razoxane, Sapporo Breweries RBS,restrictin-P, retelliptine, retinoic acid, Rhone-Poulenc RP-49532,Rhone-Poulenc RP-56976, SmithKline SK&F-104864, Sumitomo SM-108, KuraraySMANCS, SeaPharm SP-10094, spatol, spirocyclopropane derivatives,spirogermanium, Unimed, SS Pharmaceutical SS-554, strypoldinone,Stypoldione, Suntory SUN 0237, Suntory SUN 2071, superoxide dismutase,Toyama T-506, Toyama T-680, taxol, Teijin TEI-0303, teniposide,thaliblastine, Eastman Kodak TJB-29, tocotrienol, topotecan, Topostin,Teijin TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028, ukrain, EastmanKodak USB-006, vinblastine sulfate, vincristine, vindesine,vinestramide, vinorelbine, vintriptol, vinzolidine, withanolides andYamanouchi YM-534.

Alternatively, the present compounds may also be used in co-therapieswith other anti-neoplastic agents, such as acemannan, aclarubicin,aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine,aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole,ANCER, ancestim, ARGLABIN, arsenic trioxide, BAM 002 (Novelos),bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin,cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, DA 3030(Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane,dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine,doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HITdiclofenac, interferon alfa, daunorubicin, doxorubicin, tretinoin,edelfosine, edrecolomab, eflornithine, emitefur, epirubicin, epoetinbeta, etoposide phosphate, exemestane, exisulind, fadrozole, filgrastim,finasteride, fludarabine phosphate, formestane, fotemustine, galliumnitrate, gemcitabine, gemtuzumab zogamicin, gimeracil/oteracil/tegafurcombination, glycopine, goserelin, heptaplatin, human chorionicgonadotropin, human fetal alpha fetoprotein, ibandronic acid,idarubicin, (imiquimod, interferon alfa, interferon alfa, natural,interferon alfa-2, interferon alfa-2a, interferon alfa-2b, interferonalfa-N1, interferon alfa-n3, interferon alfacon-1, interferon alpha,natural, interferon beta, interferon beta-1a, interferon beta-1b,interferon gamma, natural interferon gamma-1a, interferon gamma-1b,interleukin-1 beta, iobenguane, irinotecan, irsogladine, lanreotide, LC9018 (Yakult), leflunomide, lenograstim, lentinan sulfate, letrozole,leukocyte alpha interferon, leuprorelin, levamisole+fluorouracil,liarozole, lobaplatin, lonidamine, lovastatin, masoprocol, melarsoprol,metoclopramide, mifepristone, miltefosine, mirimostim, mismatched doublestranded RNA, mitoguazone, mitolactol, mitoxantrone, molgramostim,nafarelin, naloxone+pentazocine, nartograstim, nedaplatin, nilutamide,noscapine, novel erythropoiesis stimulating protein, NSC 631570octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel, pamidronicacid, pegaspargase, peginterferon alfa-2b, pentosan polysulfate sodium,pentostatin, picibanil, pirarubicin, rabbit antithymocyte polyclonalantibody, polyethylene glycol interferon alfa-2a, porfimer sodium,raloxifene, raltitrexed, rasburicase, rhenium Re 186 etidronate, RIIretinamide, rituximab, romurtide, samarium (153 Sm) lexidronam,sargramostim, sizofuran, sobuzoxane, sonermin, strontium-89 chloride,suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide,teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropinalfa, topotecan, toremifene, tositumomab-iodine 131, trastuzumab,treosulfan, tretinoin, trilostane, trimetrexate, triptorelin, tumornecrosis factor alpha, natural, ubenimex, bladder cancer vaccine,Maruyama vaccine, melanoma lysate vaccine, valrubicin, verteporfin,vinorelbine, VIRULIZIN, zinostatin stimalamer, or zoledronic acid;abarelix; AE 941 (Aeterna), ambamustine, antisense oligonucleotide,bcl-2 (Genta), APC 8015 (Dendreon), cetuximab, decitabine,dexaminoglutethimide, diaziquone, EL 532 (Elan), EM 800 (Endorecherche),eniluracil, etanidazole, fenretinide, filgrastim SDO1 (Amgen),fulvestrant, galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy(Vical), granulocyte macrophage colony stimulating factor, histaminedihydrochloride, ibritumomab tiuxetan, ilomastat, IM 862 (Cytran),interleukin-2, iproxifene, LDI 200 (Milkhaus), leridistim, lintuzumab,CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development),HER-2 and Fc MAb (Medarex), idiotypic 105AD7 MAb (CR^(C) Technology),idiotypic CEA MAb (Trilex), LYM-1-iodine 131 MAb (Techniclone),polymorphic epithelial mucin-yttrium 90 MAb (Antisoma), marimastat,menogaril, mitumomab, motexafin gadolinium, MX 6 (Galderma), nelarabine,nolatrexed, P 30 protein, pegvisomant, pemetrexed, porfiromycin,prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodiumphenylacetate, sparfosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN), TA077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, tinethyl etiopurpurin, tirapazamine, cancer vaccine (Biomira), melanomavaccine (New York University), melanoma vaccine (Sloan KetteringInstitute), melanoma oncolysate vaccine (New York Medical College),viral melanoma cell lysates vaccine (Royal Newcastle Hospital), orvalspodar.

Alternatively, the present compounds may also be used in co-therapieswith VEGFR inhibitors including

-   N-(4-chlorophenyl)-4-(4-pyridinylmethyl)-1-phthalazinamine;-   4-[4-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2-pyridinecarboxamide;-   N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide;-   3-[(4-bromo-2,6-difluorophenyl)methoxy]-5-[[[[4-(1-pyrrolidinyl)butyl]amino]carbonyl]amino]-4-isothiazolecarboxamide;-   N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methyl-4-piperidinyl)methoxy]-4-quinazolinamine;-   3-[5,6,7,13-tetrahydro-9-[(1-methylethoxy)methyl]-5-oxo-12H-indeno[2,1-a]pyrrolo[3,4-c]carbazol-12-yl]propyl    ester N,N-dimethyl-glycine;-   N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide;-   N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[[[2-(methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine-   4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-phenyl]benzamide-   N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy]-4-quinazolinamine-   N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine-   N-(3-((((2R)-1-methyl-2-pyrrolidinyl)methyl)oxy)-5-(trifluoromethyl)phenyl)-2-((3-(1,3-oxazol-5-yl)phenyl)amino)-3-pyridinecarboxamide;-   2-(((4-fluorophenyl)methyl)amino)-N-(3-((((2R)-1-methyl-2-pyrrolidinyl)methyl)oxy)-5-(trifluoromethyl)phenyl)-3-pyridinecarboxamide;-   N-[3-(Azetidin-3-ylmethoxy)-5-trifluoromethyl-phenyl]-2-(4-fluoro-benzylamino)-nicotinamide.-   6-fluoro-N-(4-(1-methylethyl)phenyl)-2-((4-pyridinylmethyl)amino)-3-pyridinecarboxamide;-   2-((4-pyridinylmethyl)amino)-N-(3-(((2S)-2-pyrrolidinylmethyl)oxy)-5-(trifluoromethyl)phenyl)-3-pyridinecarboxamide;-   N-(3-(1,1-dimethylethyl)-1H-pyrazol-5-yl)-2-((4-pyridinylmethyl)amino)-3-pyridinecarboxamide;-   N-(3,3-dimethyl-2,3-dihydro-1-benzofuran-6-yl)-2-((4-pyridinylmethyl)amino)-3-pyridinecarboxamide;-   N-(3-((((2S)-1-methyl-2-pyrrolidinyl)methyl)oxy)-5-(trifluoromethyl)phenyl)-2-((4-pyridinylmethyl)amino)-3-pyridinecarboxamide;-   2-((4-pyridinylmethyl)amino)-N-(3-((2-(1-pyrrolidinyl)ethyl)oxy)-4-(trifluoromethyl)phenyl)-3-pyridinecarboxamide;-   N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-((4-pyridinylmethyl)amino)-3-pyridinecarboxamide;-   N-(4-(pentafluoroethyl)-3-(((2S)-2-pyrrolidinylmethyl)oxy)phenyl)-2-((4-pyridinylmethyl)amino)-3-pyridinecarboxamide;-   N-(3-((3-azetidinylmethyl)oxy)-5-(trifluoromethyl)phenyl)-2-((4-pyridinylmethyl)amino)-3-pyridinecarboxamide;-   N-(3-(4-piperidinyloxy)-5-(trifluoromethyl)phenyl)-2-((2-(3-pyridinyl)ethyl)amino)-3-pyridinecarboxamide;-   N-(4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-2-(1H-indazol-6-ylamino)-nicotinamide;-   2-(1H-indazol-6-ylamino)-N-[3-(1-methylpyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide;-   N-[1-(2-dimethylamino-acetyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-2-(1H-indazol-6-ylamino)-nicotinamide;-   2-(1H-indazol-6-ylamino)-N-[3-(pyrrolidin-2-ylmethoxy)-5-trifluoromethyl-phenyl]-nicotinamide;-   N-(1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-(1H-indazol-6-ylamino)-nicotinamide;-   N-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-2-(1H-indazol-6-ylamino)-nicotinamide;-   N-[4-(tert-butyl)-3-(3-piperidylpropyl)phenyl][2-(1H-indazol-6-ylamino)(3-pyridyl)]carboxamide;-   N-[5-(tert-butyl)isoxazol-3-yl][2-(1H-indazol-6-ylamino)(3-pyridyl)]carboxamide;    and-   N-[4-(tert-butyl)phenyl][2-(1H-indazol-6-ylamino)(3-pyridyl)]carboxamide.

Other compounds described in the following patents and patentapplications can be used in combination therapy: U.S. Pat. No.6,258,812, US 2003/0105091, WO 01/37820, U.S. Pat. No. 6,235,764, WO01/32651, U.S. Pat. Nos. 6,630,500, 6,515,004, 6,713,485, 5,521,184,5,770,599, 5,747,498, WO 02/68406, WO 02/66470, WO 02/55501, WO04/05279, WO 04/07481, WO 04/07458, WO 04/09784, WO 02/59110, WO99/45009, WO 00/59509, WO 99/61422, U.S. Pat. No. 5,990,141, WO 00/12089and WO 00/02871.

In some embodiments, the combination comprises a composition of thepresent invention in combination with at least one anti-angiogenicagent. Agents are inclusive of, but not limited to, in vitrosynthetically prepared chemical compositions, antibodies, antigenbinding regions, radionuclides, and combinations and conjugates thereof.An agent can be an agonist, antagonist, allosteric modulator, toxin or,more generally, may act to inhibit or stimulate its target (e.g.,receptor or enzyme activation or inhibition), and thereby promote celldeath or arrest cell growth.

Exemplary anti-tumor agents include HERCEPTIN™ (trastuzumab), which maybe used to treat breast cancer and other forms of cancer, and RITUXAN™(rituximab), ZEVALIN™ (ibritumomab tiuxetan), and LYMPHOCIDE™(epratuzumab), which may be used to treat non-Hodgkin's lymphoma andother forms of cancer, GLEEVAC™ which may be used to treat chronicmyeloid leukemia and gastrointestinal stromal tumors, and BEXXAR™(iodine 131 tositumomab) which may be used for treatment ofnon-Hodgkins's lymphoma.

Exemplary anti-angiogenic agents include ERBITUX™ (IMC-C225), KDR(kinase domain receptor) inhibitory agents (e.g., antibodies and antigenbinding regions that specifically bind to the kinase domain receptor),anti-VEGF agents (e.g., antibodies or antigen binding regions thatspecifically bind VEGF, or soluble VEGF receptors or a ligand bindingregion thereof) such as AVASTIN™ or VEGF-TRAP™, and anti-VEGF receptoragents (e.g., antibodies or antigen binding regions that specificallybind thereto), EGFR inhibitory agents (e.g., antibodies or antigenbinding regions that specifically bind thereto) such as ABX-EGF(panitumumab), IRESSA™ (gefitinib), TARCEVA™ (erlotinib), anti-Ang1 andanti-Ang2 agents (e.g., antibodies or antigen binding regionsspecifically binding thereto or to their receptors, e.g., Tie2/Tek), andanti-Tie2 kinase inhibitory agents (e.g., antibodies or antigen bindingregions that specifically bind thereto). The pharmaceutical compositionsof the present invention can also include one or more agents (e.g.,antibodies, antigen binding regions, or soluble receptors) thatspecifically bind and inhibit the activity of growth factors, such asantagonists of hepatocyte growth factor (HGF, also known as ScatterFactor), and antibodies or antigen binding regions that specificallybind its receptor “c-met”.

Other anti-angiogenic agents include Campath, IL-8, B-FGF, Tekantagonists (Ceretti et al., US Publication No. 2003/0162712; U.S. Pat.No. 6,413,932), anti-TWEAK agents (e.g., specifically binding antibodiesor antigen binding regions, or soluble TWEAK receptor antagonists; see,Wiley, U.S. Pat. No. 6,727,225), ADAM distintegrin domain to antagonizethe binding of integrin to its ligands (Fanslow et al., US PublicationNo. 2002/0042368), specifically binding anti-eph receptor and/oranti-ephrin antibodies or antigen binding regions (U.S. Pat. Nos.5,981,245; 5,728,813; 5,969,110; 6,596,852; 6,232,447; 6,057,124 andpatent family members thereof), and anti-PDGF-BB antagonists (e.g.,specifically binding antibodies or antigen binding regions) as well asantibodies or antigen binding regions specifically binding to PDGF-BBligands, and PDGFR kinase inhibitory agents (e.g., antibodies or antigenbinding regions that specifically bind thereto).

Additional anti-angiogenic/anti-tumor agents include: SD-7784 (Pfizer,USA); cilengitide. (Merck KGaA, Germany, EPO 770622); pegaptaniboctasodium, (Gilead Sciences, USA); Alphastatin, (BioActa, UK); M-PGA,(Celgene, USA, U.S. Pat. No. 5,712,291); ilomastat, (Arriva, USA, U.S.Pat. No. 5,892,112); emaxanib, (Pfizer, USA, U.S. Pat. No. 5,792,783);vatalanib, (Novartis, Switzerland); 2-methoxyestradiol, (EntreMed, USA);TLC ELL-12, (Elan, Ireland); anecortave acetate, (Alcon, USA);alpha-D148 Mab, (Amgen, USA); CEP-7055, (Cephalon, USA); anti-Vn Mab,(Crucell, Netherlands) DAC:antiangiogenic, (ConjuChem, Canada);Angiocidin, (InKine Pharmaceutical, USA); KM-2550, (Kyowa Hakko, Japan);SU-0879, (Pfizer, USA); CGP-79787, (Novartis, Switzerland, EP 970070);ARGENT technology, (Ariad, USA); YIGSR-Stealth, (Johnson & Johnson,USA); fibrinogen-E fragment, (BioActa, UK); angiogenesis inhibitor,(Trigen, UK); TBC-1635, (Encysive Pharmaceuticals, USA); SC-236,(Pfizer, USA); ABT-567, (Abbott, USA); Metastatin, (EntreMed, USA);angiogenesis inhibitor, (Tripep, Sweden); maspin, (Sosei, Japan);2-methoxyestradiol, (Oncology Sciences Corporation, USA); ER-68203-00,(IVAX, USA); Benefin, (Lane Labs, USA); Tz-93, (Tsumura, Japan);TAN-1120, (Takeda, Japan); FR-111142, (Fujisawa, Japan, JP 02233610);platelet factor 4, (RepliGen, USA, EP 407122); vascular endothelialgrowth factor antagonist, (Borean, Denmark); cancer therapy, (Universityof South Carolina, USA); bevacizumab (pINN), (Genentech, USA);angiogenesis inhibitors, (SUGEN, USA); XL 784, (Exelixis, USA); XL 647,(Exelixis, USA); MAb, alpha5beta3 integrin, second generation, (AppliedMolecular Evolution, USA and MedImmune, USA); gene therapy, retinopathy,(Oxford BioMedica, UK); enzastaurin hydrochloride (USAN), (Lilly, USA);CEP 7055, (Cephalon, USA and Sanofi-Synthelabo, France); BC 1, (GenoaInstitute of Cancer Research, Italy); angiogenesis inhibitor, (Alchemia,Australia); VEGF antagonist, (Regeneron, USA); rBPI 21 and BPI-derivedantiangiogenic, (XOMA, USA); PI 88, (Progen, Australia); cilengitide(pINN), (Merck KGaA, German; Munich Technical University, Germany,Scripps Clinic and Research Foundation, USA); cetuximab (INN), (Aventis,France); AVE 8062, (Ajinomoto, Japan); AS 1404, (Cancer ResearchLaboratory, New Zealand); SG 292, (Telios, USA); Endostatin, (BostonChildrens Hospital, USA); ATN 161, (Attenuon, USA); ANGIOSTATIN, (BostonChildrens Hospital, USA); 2-methoxyestradiol, (Boston ChildrensHospital, USA); ZD 6474, (AstraZeneca, UK); ZD 6126, (AngiogenePharmaceuticals, UK); PPI 2458, (Praecis, USA); AZD 9935, (AstraZeneca,UK); AZD 2171, (AstraZeneca, UK); vatalanib (pINN), (Novartis,Switzerland and Schering AG, Germany); tissue factor pathway inhibitors,(EntreMed, USA); pegaptanib (Pinn), (Gilead Sciences, USA);xanthorrhizol, (Yonsei University, South Korea); vaccine, gene-based,VEGF-2, (Scripps Clinic and Research Foundation, USA); SPV5.2,(Supratek, Canada); SDX 103, (University of California at San Diego,USA); PX 478, (ProIX, USA); METASTATIN, (EntreMed, USA); troponin I,(Harvard University, USA); SU 6668, (SUGEN, USA); OXI 4503, (OXiGENE,USA); o-guanidines, (Dimensional Pharmaceuticals, USA); motuporamine C,(British Columbia University, Canada); CDP 791, (Celltech Group, UK);atiprimod (pINN), (GlaxoSmithKline, UK); E 7820, (Eisai, Japan); CYC381, (Harvard University, USA); AE 941, (Aeterna, Canada); vaccine,angiogenesis, (EntreMed, USA); urokinase plasminogen activatorinhibitor, (Dendreon, USA); oglufanide (pINN), (Melmotte, USA);HIF-1alfa inhibitors, (Xenova, UK); CEP 5214, (Cephalon, USA); BAY RES2622, (Bayer, Germany); Angiocidin, (InKine, USA); A6, (Angstrom, USA);KR31372, (Korea Research Institute of Chemical Technology, South Korea);GW 2286, (GlaxoSmithKline, UK); EHT 0101, (ExonHit, France); CP 868596,(Pfizer, USA); CP 564959, (OSI, USA); CP 547632, (Pfizer, USA); 786034,(GlaxoSmithKline, UK); KRN 633, (Kirin Brewery, Japan); drug deliverysystem, intraocular, 2-methoxyestradiol, (EntreMed, USA); anginex,(Maastricht University, Netherlands, and Minnesota University, USA); ABT510, (Abbott, USA); AAL 993, (Novartis, Switzerland); VEGI,(ProteomTech, USA); tumor necrosis factor-alpha inhibitors, (NationalInstitute on Aging, USA); SU 11248, (Pfizer, USA and SUGEN USA); ABT518, (Abbott, USA); YH16, (Yantai Rongchang, China); S-3APG, (BostonChildrens Hospital, USA and EntreMed, USA); MAb, KDR, (ImClone Systems,USA); MAb, alpha5 beta1, (Protein Design, USA); KDR kinase inhibitor,(Celltech Group, UK, and Johnson & Johnson, USA); GFB 116, (SouthFlorida University, USA and Yale University, USA); CS 706, (Sankyo,Japan); combretastatin A4 prodrug, (Arizona State University, USA);chondroitinase AC, (IBEX, Canada); BAY RES 2690, (Bayer, Germany); AGM1470, (Harvard University, USA, Takeda, Japan, and TAP, USA); AG 13925,(Agouron, USA); Tetrathiomolybdate, (University of Michigan, USA);GCS100, (Wayne State University, USA) CV 247, (Ivy Medical, UK); CKD732, (Chong Kun Dang, South Korea); MAb, vascular endothelium growthfactor, (Xenova, UK); irsogladine (INN), (Nippon Shinyaku, Japan); RG13577, (Aventis, France); WX 360, (Wilex, Germany); squalamine (pINN),(Genaera, USA); RPI 4610, (Sima, USA); cancer therapy, (Marinova,Australia); heparanase inhibitors, (InSight, Israel); KL 3106, (Kolon,South Korea); Honokiol, (Emory University, USA); ZK CDK, (Schering AG,Germany); ZK Angio, (Schering AG, Germany); ZK 229561, (Novartis,Switzerland, and Schering AG, Germany); XMP 300, (XOMA, USA); VGA 1102,(Taisho, Japan); VEGF receptor modulators, (Pharmacopeia, USA);VE-cadherin-2 antagonists, (ImClone Systems, USA); Vasostatin, (NationalInstitutes of Health, USA); vaccine, Flk-1, (ImClone Systems, USA); TZ93, (Tsumura, Japan); TurnStatin, (Beth Israel Hospital, USA); truncatedsoluble FLT 1 (vascular endothelial growth factor receptor 1), (Merck &Co, USA); Tie-2 ligands, (Regeneron, USA); and, thrombospondin 1inhibitor, (Allegheny Health, Education and Research Foundation, USA).

Alternatively, the present compounds may also be used in co-therapieswith other anti-neoplastic agents, such as VEGF antagonists, otherkinase inhibitors including p38 inhibitors, KDR inhibitors, EGFinhibitors and CDK inhibitors, TNF inhibitors, metallomatrix proteasesinhibitors (MMP), COX-2 inhibitors including celecoxib, NSAID's, orα_(v)β₃ inhibitors.

The present invention comprises processes for the preparation of acompound of Formula I, II, III, IV, V, VI and VII.

Also included in the family of compounds of the current are thepharmaceutically acceptable salts and solvates thereof. The term“pharmaceutically-acceptable salts” embraces salts commonly used to formalkali metal salts and to form addition salts of free acids or freebases. The nature of the salt is not critical, provided that it ispharmaceutically acceptable. Suitable pharmaceutically acceptable acidaddition salts of compounds of the current invention may be preparedfrom an inorganic acid or from an organic acid. Examples of suchinorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric,carbonic, sulfuric and phosphoric acid. Appropriate organic acids may beselected from aliphatic, cycloaliphatic, aromatic, arylaliphatic,heterocyclic, carboxylic and sulfonic classes of organic acids, exampleof which are formic, acetic, adipic, butyric, propionic, succinic,glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic(pamoic), methanesulfonic, ethanesulfonic, ethanedisulfonic,benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic,sulfanilic, cyclohexylaminosulfonic, camphoric, camphorsulfonic,digluconic, cyclopentanepropionic, dodecylsulfonic, glucoheptanoic,glycerophosphonic, heptanoic, hexanoic, 2-hydroxy-ethanesulfonic,nicotinic, 2-naphthalenesulfonic, oxalic, palmoic, pectinic,persulfuric, 2-phenylpropionic, picric, pivalic propionic, succinic,tartaric, thiocyanic, mesylic, undecanoic, stearic, algenic,β-hydroxybutyric, salicylic, galactaric and galacturonic acid. Suitablepharmaceutically-acceptable base addition salts of compounds of thecurrent invention include metallic salts, such as salts made fromaluminum, calcium, lithium, magnesium, potassium, sodium and zinc, orsalts made from organic bases including primary, secondary and tertiaryamines, substituted amines including cyclic amines, such as caffeine,arginine, diethylamine, N-ethyl piperidine, aistidine, glucamine,isopropylamine, lysine, morpholine, N-ethyl morpholine, piperazine,piperidine, tri ethyl amine, trimethyl amine. All of these salts may beprepared by conventional means from the corresponding compound of theinvention by reacting, for example, the appropriate acid or base withthe compound of the current invention. When a basic group and an acidgroup are present in the same molecule, a compound of the currentinvention may also form internal salts.

General Synthetic Procedures

The compounds of the invention can be synthesized according to thefollowing procedures.

The following abbreviations are used throughout the specification:

The following abbreviations are used throughout the specification: HOAcacetic acid MeCN, CH₃CN acetonitrile NH₃ ammonia NH₄Cl ammonium chlorideAr argon HBTA O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate PyBopbenzotriazol-1-yl-oxy-tripyrrolidino-phosphonium hexafluorophosphatePd₂(dba)₃ bis(dibenzylideneacetone) palladium BINAP2,2′-bis(diphenylphosphino)-1,1′-binaphthyl TEACbis(tetra-ethylammonium)carbonate BBr₃ boron tribromide BSA bovine serumalbumin Br₂ bromine BOC butyloxycarbonyl Cs₂CO₃ cesium carbonate CHCl₃chloroform CDCl₃ chloroform deuterated Cu copper CuI copper(I) iodideEt₂O diethyl ether DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DIBALdiisobutylaluminum hydride DIAD diisopropyl azodicarboxylate DIEAdiisopropylethylamine DMF dimethylformamide DMAP 4-dimethylaminopyridineDMSO dimethylsulfoxide EDC, EDCI1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride dppadiphenylphosphoryl azide EtOAc ethyl acetate FBS fetal bovine serum ggram h hour HBr hydrobromic acid HCl hydrochloric acid HOBt1-hydroxybenzotriazole hydrate H₂ hydrogen H₂O₂ hydrogen peroxide Feiron LiHMDS lithium bis(trimethylsilyl)-amide LDA Lithiumdiisopropylamide MCPBA meta-chloroperbenzoic acid MgSO₄ magnesiumsulfate MeOH, CH₃OH methanol MeI methyl iodide CH₂Cl₂, DCM methylenechloride NMP N-methylpyrrolidinone ML, ml milliliter N₂ nitrogen Pd/Cpalladium on carbon Pd(OAc)₂ palladium acetate Pd(OH)₂ palladiumhydroxide Pd(PPh₃)₄ palladium tetrakis triphenylphosphine Pd(dppf)Cl₂1,1-bis(diphenylphosphino)ferrocene palladium chloride PBS phosphatebuffered saline POCl₃ phosphorous oxychloride K₂CO₃ potassium carbonateKOH potassium hydroxide RT room temperature NaHCO₃ sodium bicarbonateNaBH₄ sodium borohydride NaBH₃CN sodium cyanoborohydride NaOtBu sodiumtert-butoxide NaOH sodium hydroxide NaClO₂ sodium chlorite NaCl sodiumchloride NaHPO₄ sodium biphospate NaH sodium hydride NaI sodium iodideNa₂SO₄ sodium sulfate TBTUO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate THFtetrahydrofuran Et₃N, TEA triethylamine TFA trifluoroacetic acidP(t-bu)₃ tri(tert-butyl)phosphine H₂O water

EXAMPLE 14-((6-(3-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline

Step 1.

2-(7-methoxyquinolin-4-yloxy)acetic acid

A 250-mL, 3-neck, rb flask equipped with a magnetic stirbar, a refluxcondenser and a powder funnel was charged with potassium hydroxide (6.0g, 90 mmol) then 2-hydroxyacetic acid (5.0 g, 65 mmol) with stirring.The solid reactants gradually reacted and liquified as significant heatwas generated. Upon dissolution of all the reagents, flask containingthe hot syrupy liquid was immersed in a 170° C. oil bath, then asolution of 4-chloro-7-methoxyquinoline (5.0 g, 26 mmol) in anhydrousDMSO (20 mL, 4 vol wrt quinoline) was added dropwise over 20-30 min viaaddition funnel. The resulting brown solution was maintained in the oilbath with stirring. After 2.5 h, the flask was removed from the oilbath, then quenched by the addition of water (100 mL, 5 vol wrt DMSO).The resulting brown solution was immersed in an ice bath, and themixture was neutralized by the dropwise addition of 6 N HCl (15 mL, 1equiv to KOH), which resulted in the formation of a thick yellow ppt andbrought the mixture to pH 3. The mixture was filtered and washed withwater and ACN. The solid products were dried under vacuum to yield2-(7-methoxyquinolin-4-yloxy)acetic acid (2.16 g, 36% yield) as a yellowsolid. (ESI, pos. ion) m/z: 234.1 (M+H).

Step 2.

N′-(6-chloropyridazin-3-yl)-2-(7-methoxyquinolin-4-yloxy)acetohydrazide

A mixture of 1-(6-chloropyridazin-3-yl)hydrazine (0.372 g, 2.57 mmol),1-hydroxy-7-aza-benzotriazole (0.350 g, 2.57 mmol), EDC (0.641 g, 3.34mmol), 2-(7-methoxyquinolin-4-yloxy)acetic acid (0.600 g, 2.57 mmol) anddiisopropylethylamine (1.34 ml, 7.72 mmol) in DMF (20 mL) was allowed tostir at 50° C. for 2 h. Concentrated. Reconstituted in MeCN (30 mL).Concentrated with cooling. Product crashed out of solution and wasisolated by filtration. Used without further purification. (ESI, pos.ion) m/z: 234.1 (M+H).

Step 3.

4-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline

N′-(6-chloropyridazin-3-yl)-2-(7-methoxyquinolin-4-yloxy)acetohydrazide(2.53 g, 7.0 mmol) was suspended in tetrahydrofuran (50 mL) then addedtriphenylphosphine (2.8 g, 11 mmol) and trimethylsilyl azide (1.4 ml, 11mmol). To this suspension, was added diethylazodicarboxylate (2.0 ml, 13mmol) in rapid drops with a syringe. The mixture became clear and hot tothe touch. The reaction mixture was heated at 50° C. for 30 minutes. Thereaction mixture was concentrated in vacuo. The remaining oil wastriturated with diethyl ether. A gel-like solid formed which wascollected on a glass frit, washing with diethyl ether. The solid wasthen triturated with ethyl acetate, and finally acetonitrile. Anamorphous solid formed which was collected on a glass frit, washing withacetonitrile. The solid was further dried under high vacuum. Inaddition, the ethyl acetate filtrate was concentrated in vacuo. Theremaining oil was then triturated with acetonitrile. An amorphous solidformed and was collected on a glass frit, washing with acetonitrile. Thesolid was further dried under high vacuum affording4-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinolineas a tan solid. MS (ESI, pos. ion) m/z: 342.1 (M+1).

Step 4.

4-((6-(3-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline

3-fluorophenylboronic acid (0.092 g, 0.66 mmol) was added to asuspension of4-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline(0.150 g, 0.44 mmol) in 2.5 mL dimethylformamide, followed by theaddition of potassium carbonate (0.18 g, 1.3 mmol) in 0.6 mL water.PdCl₂(dppf)-CH₂Cl₂ adduct (0.018 g, 0.022 mmol) was added and the flaskwas purged with argon, sealed and heated at 80° C. for four hours.Purification by MPLC (eluted with 5 then 10% MeOH in CH₂Cl₂) affordedthe product as an off-white solid (78 mg, 44%). (ESI, pos. ion) m/z:402.1 (M+H).

EXAMPLE 24-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)quinoline

Step 1.

(6-phenyl-[1,2,4-]triazolo[4,3-b]pyridazin-3-yl)methanol

A mixture of 1-(6-phenylpyridazin-3-yl)hydrazine (2.00 g, 10.7 mmol),glycolic acid (0.825 g, 10.8 mmol), p-TsOH H₂O (2.55 g, 13.4 mmol) inPhMe (50 mL) was refluxed for 14 h. PhMe was removed in vacuo. Theresulting solids were diluted with water (30 mL). The mixture wasbrought to pH˜10 with 2N NaOH. The solids were isolated solid byfiltration, washed with water and dried under vacuum to give an offwhite solid which was used without further purification. (ESI, pos. ion)m/z: 227.0 (M+H).

Step 2.

4-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)quinoline

Cesium carbonate (335 mg, 1027 μmol) was added to a mixture of4-chloroquinoline (465 mg, 2054 μmol) and above alcohol (112 mg, 685μmol) in DMSO (1.8 mL) at RT. The reaction mixture was stirred at 120°C. under microwave irradiation for 2 h. The reaction mixture was dilutedwith EtOAc and washed with water. The water layer was extracted withEtOAC. The organic layer was dried over MgSO₄, filtered and concentratedin vacuo. Purification by MPLC (CH₂Cl₂/MeOH+1% NH₄OH: 100/0 to 95/5)afforded the title compound. (ESI, pos. ion) m/z: 354.1 (M+H).

In addition to the above reaction, potassium hydride in DME can also beutilized in a similar manner.

EXAMPLE 3N-(4-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)pyridin-2-yl)pyrrolidine-1-carboxamide

Step 1.

4-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)pyridin-2-amine

To an argon purged flask was added cesium carbonate (0.24 g, 0.73 mmol),3-((2-chloropyridin-4-yloxy)methyl)-5-phenyl-3aH-pyrazolo[4,3-b]pyridine(0.0820 g, 0.24 mmol), tris(dibenzylideneacetone)dipalladium (o) (0.0056g, 0.0061 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.0091g, 0.015 mmol). The mixture was taken up in dioxane (8 mL) followed bythe addition of benzophenone imine (0.049 ml, 0.29 mmol). The mixturewas heated to reflux for 6 h. The mixture was cooled to room temperatureand filtered through a plug of silica gel which was washed with a largeamount of 10% MeOH in CH₂Cl₂. The resulting mixture was concentrated.The mixture was reconstituted in THF (5 mL) and 1M HCl (5 mL) andallowed to stir for 3 h then concentrated under reduced pressure. Theresulting residue was triturated with ether (3×20 mL) and suspended in9% sodium carbonate. The solid was isolated by filtration and utilizedwithout further purification. (ESI, pos. ion) m/z: 319.1 (M+H).

Step 2.

N-(4-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)pyridin-2-yl)pyrrolidine-1-carboxamide

To the resulting solid in THF (5 mL) was added TRIETHYLAMINE (0.17 ml,1.2 mmol) followed by phenyl chloroformate (0.15 ml, 1.2 mmol). Themixture was allowed to stir for 2 h. Added pyrrolidine (0.14 ml, 1.7mmol) and stirred for an additional 2 h. The reaction mixture wasconcentrated, reconstituted in DMSO and purified via HPLC. (ESI, pos.ion) m/z: 416.2 (M+H).

EXAMPLE 47-methoxy-N-((6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine 1)Preparation of 3-methyl-5-trimethylstannyl)isothiazole

Butyllithium (1.6M in hexanes, 18.9 ml, 30.3 mmol) was added to astirred solution of 3-methylisothiazole (2.73 g, 27.5 mmol) in THF (80mL) at −78° C. The reaction mixture was stirred at −78° C. for 30 minand chlorotrimethylstannane (1M in THF, 27.5 ml, 27.5 mmol) was addeddropwise. After 1 h at −78° C. for 1 h, the reaction mixture wasquenched with a saturated aqueous solution of NaHCO₃. The water layerwas extracted with Et₂O. The organic extracts were combined, dried overMgSO₄, filtered and concentrated in vacuo. The material (6.97 g) wastaken forward without further purification MS m/z=264.1. Calc'd for C,7; H, 13; NSSn: 261.94.

2) Preparation of tert-butyl(6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate

A pressure vessel was purged with Ar and charged with tert-butyl(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (5.00 g,17.6 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.807 g, 0.881mmol), 2-dicyclohexylphosphinobiphenyl (0.618 g, 1.76 mmol). DMF (50 mL)was added, immediately followed by3-methyl-5-(trimethylstannyl)isothiazole (6.46 g, 24.7 mmol). Thereaction mixture was stirred at 100° C. for 1 h. Two more portions oftris(dibenzylideneacetone)dipalladium(0) (0.807 g, 0.881 mmol) and2-dicyclohexylphosphinobiphenyl (0.618 g, 1.76 mmol) were added everyhour for the first two hours of stirring. Reaction was then stirred wasat 100° C. overnight, cooled to room temperature and concentrated invacuo. Purification by MPLC (EtOAC/MeOH: 100/0 to 90/10) afforded thetitle compound (1.80 g, 30% yield). MS m/z=347.1 [M+H]⁺. Calc'd forC15H18N6O2S: 346.41

3) Preparation of(6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanamine

Trifluoroacetic acid (2889 μl, 37505 μmol) was added to a stirredsuspension of tert-butyl(6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate(464 mg, 1339 μmol) in DCM (10 mL) at RT. The reaction mixture wasstirred at RT for 45 min. and then concentrated in vacuo. 2M NH₃ in MeOHwas added. Purification by MPLC (DCM/MeOH+1% NH₄OH) afforded the titlecompound (226 mg, 69% yield). MS m/z=247.1 [M+H]⁺. Calc'd for C, 10; H,10; N, 6; S: 246.30.

4)7-methoxy-N-((6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine

(6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanamine(548 mg, 2225 μmol) and 8-chloro-3-methoxy-1,5-naphthyridine (576 mg,2959 μmol) were charged in a microwave vial. 2-butanol (7 mL) was addedand the reaction mixture was stirred at 120° C. under micro-wavesirradiation for 8 h. 2M NH₃ in MeOH was added. Purification by MPLC(DCM/MeOH+1% NH₄OH: 100/0 to 90/10) afforded the title compound (720 mg,80% yield). MS m/z=405.1 [M+H]⁺. Calc'd for C, 19; H, 16; N, 8; O, S:404.46.

EXAMPLE 57-methoxy-4-(2-(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline

Step 1.

Ethyl 3-(7-methoxyquinolin-4-yl)propanoate

4-chloro-7-methoxyquinoline (0.35 g, 2 mmol), tri-t-butylphosphoniumtetrafluoroborate (0.05 g, 0.2 mmol), andtris(dibenzylideneacetone)dipalladium (0) (0.08 g, 0.09 mmol) werecombined. The reaction vessel was purged and flushed with nitrogen threetimes, followed by addition of 3-ethoxy-3-oxopropylzinc bromide in THF(10 mL, 5 mmol, 0.5 M). The reaction mixture was microwaved at 150° C.for 60 minutes. Upon completion, ammonium hydroxide (10 mL) was added.After 30 minutes the mixture was filtered and the filtrate waspartitioned between water and ethyl acetate. Extracted with ethylacetate (3×20 mL). The organic layers were combined, washed with brine,dried over magnesium sulfate, and concentrated. Purified by MPLC with agradient of 20 to 50% EtOAc in CH₂Cl₂. (ESI, pos. ion) m/z: 354.1 (M+H).

Step 2.

7-methoxy-4-(2-(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline

Ethyl 3-(7-methoxyquinolin-4-yl)propanoate (156 mg, 0.60 mmol) wascombined with 1-(6-phenylpyridazin-3-yl)hydrazine (115 mg, 0.62 mmol)and pTsOH.H₂O (140 mg, 0.72 mmol). The mixture was microwaved at 150° C.for 60 minutes. The residue was taken up in DMSO and purified by HPLCand neutralized to yield the desired product as an off-white solid.(ESI, pos. ion) m/z: 382.1 (M+H).

EXAMPLE 6

(4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)-N,N-dimethylmethanamine.A mixture of4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)benzaldehyde(prepared according to General Method A) (0.150 g, 0.36 mmol) anddimethylamine, 2.0 m solution in thf (0.36 ml, 0.73 mmol) in THF (5 mL)was allowed to stir for 20 min. Added sodium triacetoxyborohydride (0.15g, 0.73 mmol) and stirred for 4 h. Concentrated. Suspended in DMSO,filtered through a 0.45 uM acrodisc. Purified on RPHPLC. Took fractionsthat contained product and made basic with 9% sodium carbonate. Removedvolatiles in vacuo. Product crashed out and was isolated by filtration.MS m/z=441.2 [M+1]⁺. Calc'd for C₂₅H₂₄N₆O₂: 440.2.

EXAMPLE 7

7-methoxy-4-((6-(4-(pyrrolidin-1-ylmethyl)phenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)quinoline.Prepared in a similar manner as(4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)-N,N-dimethylmethanamine.

EXAMPLE 8

4-((6-(3-fluoro-4-(morpholinomethyl)phenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline.Prepared in a similar manner as above(4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)-N,N-dimethylmethanamine.

EXAMPLE 9

2-fluoro-N-(2-methoxyethyl)-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)benzamide.A mixture of methyl2-fluoro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)benzoate(0.488 g, 1.06 mmol) (prepared according to General Method A) andlithium hydroxide hydrate (0.223 g, 5.31 mmol) in THF (20 mL), water (5mL) and MeOH (5 mL) was heated to 40° C. for 3 h. Brought to nearneutral pH with 1M HCl. Concentrated. Azeotroped with MeCN (20 mL) andPhMe (20 mL). Used without further purification. A mixture of2-methoxyethylamine (0.033 ml, 0.38 mmol), HATU (0.24 g, 0.62 mmol),Hunig's Base (0.24 ml, 1.4 mmol),2-fluoro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)benzoicacid (0.153 g, 0.34 mmol) in DMF was allowed to stir at room temperaturefor 1 h. Concentrated. Purified on RPHPLC. Took fractions containingproduct and made basic with 9% sodium carbonate. The volatiles wereremoved in vacuo and the product was isolated by filtration. Dried undervacuum. MS m/z=503.2 [M+1]⁺. Calc'd for C₂₆H₂₃FN₆O₄: 502.5.

EXAMPLE 10

2-fluoro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-N,N-dimethylbenzamide.Prepared in a similar manner as2-fluoro-N-(2-methoxyethyl)-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)benzamide.

EXAMPLE 11

2-fluoro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)benzamide.Prepared in a similar manner as2-fluoro-N-(2-methoxyethyl)-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)benzamide.

EXAMPLE 12

4-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)quinoline-7-carboxamide.A mixture of4-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)quinoline-7-carbonitrile(0.300 g, 0.793 mmol) and SULFURIC ACID (3.00 ml, 56.3 mmol) was heatedat 90° C. for 30 min. Quenched onto ice and sodium bicarbonate. Isolatedsolid by filtration and purified on RPHPLC. Fractions containing productwere treated with 9% sodium carbonate. Removed volatiles. Productcrashed out and was isolated by filtration. MS m/z=397.1 [M+1]⁺. Calc'dfor C₂₂H₁₆N₆O₂: 396.4.

EXAMPLE 13

1-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1H-[1,2,3]triazolo[4,5-c]pyridine.Step 1. To a solution of ethyl 2-(3-nitropyridin-4-ylamino)acetate (1.41g, 6.26 mmol) (prepared according to J. Med. Chem. (1991), 34, 2993.) inTHF (10 mL), MeOH (10 mL) and water (5 mL) at 0° C. was added lithiumhydroxide, monohydrate (0.522 ml, 18.8 mmol). Stirred at 0° C. for 30min. Acidified to pH˜4 with conc. HCl. Concentrated. Azeotroped withMeCN (40 mL) followed by PhMe (30 mL). Took up in DMF (30 mL). Added1-(6-phenylpyridazin-3-yl)hydrazine (1.17 g, 6.26 mmol),diisopropylethylamine (3.27 ml, 18.8 mmol) followed by HATU (3.57 g,9.39 mmol). Stirred for 30 min. Concentrated. Partitioned between DCM(30 mL) and water (30 mL). Filtered and isolated solid material. Washedwith water (10 mL) and DCM (10 mL). Dried under vacuum. MS m/z=366.1[M+1]⁺. Calc'd for C₁₇H₁₅N₇O₃: 365.4.

Step 2. To a mixture of2-(3-nitropyridin-4-ylamino)-N′-(6-phenylpyridazin-3-yl)acetohydrazide(0.663 g, 1.81 mmol), triphenylphosphine (0.952 g, 3.63 mmol) andtrimethylsilyl azide (0.482 ml, 3.63 mmol) in THF (10 mL) at roomtemperature was added diisopropyl azodicarboxylate (0.715 ml, 3.63mmol). Heated to ˜70° C. for 30 min. Reaction is complete. Concentrated.Purified on silica gel. 0 to 7% MeOH in CH₂Cl₂ with 1% NH₄OH. MSm/z=348.1 [M+1]⁺. Calc'd for C₁₇H₁₃N₇O₂: 347.3.

Step 3. To a mixture of3-nitro-N-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)pyridin-4-amine(0.373 g, 1.07 mmol) in THF (10 mL), MeOH (5 mL), EtOH (10 mL) was addedRaney Nickel (wet, washed, ˜1 g wet). Stirred for 20 min. Reaction iscomplete. Filtered through a 0.45 μm acrodisc. Concentrated. Usedwithout further purification. MS m/z=318.1 [M+1]⁺. Calc'd for C₁₇H₁₅N₇:317.4.

Step 3. To a solution ofN4-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)pyridine-3,4-diamine(0.0640 g, 0.202 mmol) in HOAc (5 mL) was added sodium nitrite (0.0153g, 0.222 mmol) in water (2 mL). Stirred for 1 h. Concentrated. Took upin DMSO and purified on RPHPLC. Took fractions containing product andmade basic with 9% sodium carbonate and removed volatiles in vacuo.Product crashed out and was isolated by filtration. MS m/z=329.2 [M+1]⁺.Calc'd for C₁₇H₁₂N₈: 328.3.

EXAMPLE 14

3-((1H-imidazo[4,5-c]pyridin-1-yl)methyl)-6-phenyl-[1,2,4]triazolo[4,3-b]pyridazine.A mixture ofN4-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)pyridine-3,4-diamine(0.0650 g, 0.20 mmol), triethyl orthoformate (5.0 ml, 30 mmol), andp-TsOH (0.0039 g, 0.020 mmol) was heated at 60° C. After 2 h reaction iscomplete. Reaction was concentrated. Took up in DMSO and purified onRPHPLC. Fractions containing product were treated with 9% sodiumcarbonate and volatiles removed. Collected product by filtration. MSm/z=328.1 [M+1]⁺. Calc'd for C₁₈H₁₃N₇: 327.3.

EXAMPLE 15

4-((6-(3-fluoro-4-(2-morpholinoethoxy)phenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline.To a mixture of 4-(2-hydroxyethyl)morpholine (0.0964 ml, 0.788 mmol),triphenylphosphine (0.238 g, 0.909 mmol),2-fluoro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenol(0.253 g, 0.606 mmol)(prepared according to General Method A) in THF (10mL) was added DEAD (0.144 ml, 0.909 mmol). Stirred at room temperaturefor 1 h. Concentrated. Purified on RPHPLC. Fractions containing productwere treated with 9% sodium carbonate. Removed volatiles in vacuo.Product crashed out and was isolated by filtration. MS m/z=531.2 [M+1]⁺.Calc'd for C₂₈H₂₇FN₆O₄: 530.5.

EXAMPLE 16

2-chloro-N-(2-methoxyethyl)-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)benzamide.Prepared in a similar manner as2-fluoro-N-(2-methoxyethyl)-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)benzamide.MS m/z=519.1 [M+1]⁺. Calc'd for C₂₆H₂₃ClN₆O₄: 518.9.

EXAMPLE 17

4-((6-(3-chloro-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline.HATU (0.370 g, 0.974 mmol) and2-chloro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)benzoicacid (0.300 g, 0.650 mmol) were taken up in DMF (5 mL). Added Hunig'sBase (0.339 ml, 1.95 mmol). Stirred for 10 min. Added(Z)-N′-hydroxyacetamidine (0.289 g, 3.90 mmol). Stirred for anadditional 30 min. Removed DMF in vacuo. Suspended in water. Isolatedproduct by filtration. The resulting solid was allowed to try undervacuum. Split into 3 portions and separately took up in dioxane (4 mL)in a microwave tube and heated for 12 min at 150° C. Combined all 3reactions. Concentrated. Purified on RPHPLC. Took fractions containingproduct and made basic with 9% sodium carbonate. Removed volatiles invacuo. Product crashed out and was isolated by filtration. MS m/z=500.0[M+1]⁺. Calc'd for C₂₅H₁₈ClN₇O₃: 499.1.

EXAMPLE 18

7-methoxy-4-((6-(1-methyl-1H-1,2,3-triazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)quinoline.Step 1. Tri-t-butylphosphonium tetrafluoroborate (0.0377 g, 0.130 mmol),tris(dibenzylideneacetone)dipalladium (0.0594 g, 0.0649 mmol),trimethylsilyl acetylene (1.82 ml, 13.0 mmol),4-((6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-methoxyquinoline(0.500 g, 1.30 mmol) were taken up in dioxane (10 mL) and triethylamine(3 mL). Added CuI. Sealed in a tube and heated at 80° C. for 3 h.Concentrated. Took up in MeOH and added solid potassium carbonate (largeexcess). Allowed to stir for 30 min. Filtered through a plug of Celiteand concentrated. Took up in 10% MeOH in DCM and filtered through a plugof silica gel to afford4-((6-ethynyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-methoxyquinoline.MS m/z=331.0[M+1]⁺. Calc'd for C₁₉H₁₄N₄O₂: 330.3.

Step 2. To a mixture of4-((6-ethynyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-methoxyquinoline(0.200 g, 0.605 mmol), trimethylsilylmethyl azide (0.156 g, 1.21 mmol),sodium ascorbate (0.240 g, 1.21 mmol) in THF (4 mL) and water (1 mL) wasadded 1 drop of a copper sulfate (0.00966 g, 0.0605 mmol) solution.Stirred for 1 h. Concentrated. Suspended in water and extracted withCH₂Cl₂ (3×5 mL). Dried over sodium sulfate and concentrated. Took upcrude mixture in DMF (4 mL). Added cesium fluoride (0.368 g, 2.42 mmol)and heated to 60° for 1 h. Concentrated. Purified on RPHPLC. Fractionscontaining product were treated with 9% sodium carbonate and volatileswere removed in vacuo. Product crashed out of solution and was isolatedby filtration. MS m/z=388.1 [M+1]⁺. Calc'd for C₂₀H₁₇N₇O₂: 387.4.

EXAMPLE 19

(R/S)-7-methoxy-4-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylsulfinyl)quinoline.In a 50 mL round bottom flask under N₂ were dissolved7-methoxy-4-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylthio)quinoline(prepared according to General Method B) (220 mg, 551 μmol) in 5.5 mL ofDCM then cooled down at −78° C. and treated with solid m-CPBA (77%) (124mg, 716 μmol) then warmed slowly to rt over 3 h. The reaction mixturewas diluted with DCM then neutralized with NaHCO₃ (sat.). The aqueousphase was extracted 3× with DCM then the organic layer was dried overNa₂SO₄, filtered and concentrated under reduced pressure. The crudemixture was purified by MPLC (ISCO) with DCM/DCM:MeOH:NH₄OH(90:10:1)100:0 to 90:10 to afforded7-methoxy-4-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylsulfinyl)quinoline(109 mg, 47.6% yield) as a white solid. MS m/z=415.1 [M+1]⁺. Calc'd forC₂₂H₁₇N₅O₂S: 416.0.

EXAMPLE 20

3-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-N,N-dimethylprop-2-yn-1-amine.In a 10 mL sealed tube under N₂ were dissolveddichlorobis(triphenylphosphine)palladium (41 mg, 59 μmol),NAN-dimethylprop-2-yn-1-amine (97 mg, 1170 μmol),4-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline(prepared according to General Method A) (200 mg, 585 μmol),TRIETHYLAMINE (1631 μl, 11704 μmol) and COPPER(I) IODIDE (11 mg, 59μmol) in 3 mL of MeCN then stirred and heated at 80° C. for 10 h. Thecrude reaction mixture was directly purified by MPLC (ISCO) withDCM/DCM:MeOH:NH₄OH (90:10:1) 95:5 to afforded3-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-N,N-dimethylprop-2-yn-1-amine(26 mg, 11% yield) as a yellow solid. MS m/z=388.2[M+1]⁺. Calc'd forC₂₁H₂₀N₆O₂: 389.2.

EXAMPLE 21

8-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylamino)-1,5-naphthyridin-3-ol.In a 25 mL sealed tube was dissolved7-methoxy-N-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine(prepared according to General Method D) (300 mg, 782 μmol) in 5 mL ofconcentrated HBr then stirred and heated at 100° C. for 48 h. Thereaction mixture was diluted with DCM and H₂O then neutralized with NaOH(1N) to neutral pH. The aqueous phase was extracted 3× with DCM then theorganic layer was dried over Na₂SO₄, filtered and concentrated underreduced pressure. The crude mixture was purified by MPLC (ISCO) withDCM:MeOH:NH₄OH (90:10:1) and then triturated with hot EtOH to afforded.8-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylamino)-1,5-naphthyridin-3-ol(230 mg, 79.6% yield) as a tan solid. MS m/z=369.1 [M+1]⁺. Calc'd forC₂₀H₁₅N₇O: 370.0.

EXAMPLE 22

N-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-(2-(Pyrrolidin-1-yl)ethoxy)-1,5-naphthyridin-4-amine.In a 10 mL sealed tube under N₂ were dissolved CESIUM CARBONATE (221 mg,677 μmol),8-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylamino)-1,5-naphthyridin-3-ol(50 mg, 135 μmol), 1-(2-chloroethyl)pyrrolidine hydrochloride (46 mg,271 μmol) and SODIUM IODIDE (41 mg, 271 μmol) in 1 mL of DMSO thenstirred and heated at 75° C. for 3 h. The reaction mixture was dilutedwith H₂O and the aqueous phase was extracted 3× with DCM then theorganic layer was dried over Na₂SO₄, filtered and concentrated underreduced pressure. The crude mixture was purified by MPLC (ISCO) withDCM/DCM:MeOH:NH₄OH (90:10:1)100:0 to 90:10 to affordedN-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-(2-(pyrrolidin-1-yl)ethoxy)-1,5-naphthyridin-4-amine(7 mg, 11% yield) as a yellow solid. MS m/z=466.2 [M+1]⁺. Calc'd forC₂₆H₂₆N₈O: 467.0.

EXAMPLE 237-Methoxy-4-((5-phenyl-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)quinoline

a) 5-Phenyl-[1,2,3]triazolo[1,5-a]pyridine-3-carboxylate. To a solutionof methyl 2-(4-phenylpyridin-2-yl)acetate (see Lohse, O.; Thevenin, P.;Waldvogel, E. Synlett 1999, 1, 45-48) (0.504 g, 2.22 mmol) in 12 mLCH₃CN was added DBU (0.501 ml, 3.33 mmol) and the mixture cooled in anice bath. To the solution, 4-acetamidobenzenesulfonyl azide (0.533 g,2.22 mmol) was added and the mixture allowed to warm to rt. The mixturewas stirred at rt for 5 h then evaporated. The residue was diluted withCH₂Cl₂, washed with water, brine, dried over Na₂SO₄, and filtered. Thetitle compound was obtained after purification via flash chromatography.

b) (5-Phenyl-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methanol. To a cooled(ice bath) suspension of lithium tetrahydroaluminate (0.0929 g, 2.45mmol) in 2 mL THF (anhy) was added slowly a solution of methyl5-phenyl-[1,2,3]triazolo[1,5-a]pyridine-3-carboxylate (0.310 g, 1.22mmol) in 20 mL THF (internal temp remained <20 C). The mixture wasallowed to stir in the ice bath 10 minutes. The mixture was diluted withEtOAc, washed with water, sat. NaHCO₃, the organic layer dried overNa₂SO₄, and filtered. The aqueous layer still had uv activity so asolution of Rochelle's salt and EA were added and the mixture stirred 30min. The organic layer was washed with sat NaHCO₃, dried over Na₂SO₄,filtered, combined with main portion and evaporated. The title compoundwas isolated as a yellow solid.

c)7-Methoxy-4-((5-phenyl-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)quinoline.A sealable tube was charged with Pd₂ dba₃ (0.219 g, 0.239 mmol),di-tert-butyl(1-(naphthalen-1-yl)naphthalen-2-yl)phosphine (0.190 g,0.477 mmol), (5-phenyl-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methanol(0.215 g, 0.955 mmol), 4-chloro-7-methoxyquinoline (0.222 g, 1.15 mmol),Cs₂CO₃ (0.622 g, 1.91 mmol) and dioxane (3 mL). The tube was blanketedwith N₂, sealed and heated at 100 C for 45 min. The mixture was allowedto cool to rt and evaporated. The residue was purified via flashchromatography using a 1% NH₄OH in MeOH in CH₂Cl₂ gradient. The titlecompound was collected as a tan solid. M/Z=405.1 [M+Na], calc 382.415for C₂₃H₁₈N₄O₂.

EXAMPLE 24N-((6-(3-Chloro-4-fluorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine

a) N′-(5-bromopyridin-2-yl)-2-(tert-butoxycarbonylamino)acetohydrazide.A suspension of 1-(5-bromopyridin-2-yl)hydrazine (4.00 g, 21 mmol),2-(tert-butoxycarbonyl)acetic acid (3.7 g, 21 mmol), and HATU (12 g, 32mmol) in 50 mL CH₃CN was cooled to −78 (solid precipitates to preventstirring). The flask was removed from bath gradually allow to warm. Whenstirring resumed, triethylamine (8.9 ml, 64 mmol) was added and themixture stirred for 1 h, then evaporated. The residue was dissolved withCH₂Cl₂, washed with water, brine, and the organic layer dried overNa₂SO₄, filtered and evaporated. The mixture was purified via flashchromatography using a EtOAc in hexanes gradient. The title compound wascollected as a yellow oil.

b) tert-Butyl(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methylcarbamate. To asolution ofN′-(5-bromopyridin-2-yl)-2-(tert-butoxycarbonylamino)acetohydrazide (2.2g, 6.4 mmol) in THF (30 mL) was added triphenylphosphine (2.5 g, 9.6mmol) and TMS azide (1.3 ml, 9.6 mmol). DEAD (1.8 ml, 11 mmol) was addeddropwise rapidly and the mixture heated at 55 C 1 h. The solvent wasevaporated and the residue dissolved in CH₂Cl₂, washed with water,brine, dried over Na₂SO₄, and filtered. The mixture was purified viaflash chromatography using a EtOAc in CH₂Cl₂ gradient. The titlecompound obtained as a tan solid (664 mg, 32%).

c)N-((6-Bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine.To a suspension of tert-butyl(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methylcarbamate (0.900 g,2.75 mmol) in CH₂Cl₂ (10 mL) was added TFA (0.848 ml, 11.0 mmol) and themixture stirred at rt. After 30 minutes additional TFA (0.848 ml, 11.0mmol) was added, and the mixture stirred at rt 2 h more thenconcentrated. The residue was taken up into 2-butanol (5 mL) andcombined with 8-chloro-3-methoxy-1,5-naphthyridine (0.535 g, 2.75 mmol)in a 5 mL microwave vessel. The vessel was sealed and the mixture heatedin the microwave for 10 min at 120 C with a 60 sec prestir. The mixturewas concentrated, diluted with DCM and stirred with 2N NaOH (pH 14) for30 minutes. The solid was filtered to afford the title compound as abeige solid.

d)N-((6-(3-Chloro-4-fluorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine.A sealable tube was charged with PdCl₂(dppf)-CH₂Cl₂ Adduct (0.064 g,0.078 mmol),N-((6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine(0.120 g, 0.31 mmol), 3-chloro-4-fluorophenylboronic acid (0.057 g, 0.33mmol), sat NaHCO₃ (0.75 ml, >0.69 mmol) and dioxane (2 mL). The vesselwas sealed and the mixture heated at 80 for 2.5 h. The mixture wasallowed to cool to rt and diluted with water, causing a tan solid toprecipitate. CH₂Cl₂ (1 mL) was added and the solid filtered. The titlecompound was obtained after purification via flash chromatography (usinga MeOH in CH₂Cl₂ gradient) as a tan solid. M/Z=435.1 [M+H], calc434.8604 for C₂₂H₁₆ClFN₆O.

The following compounds were prepared using the same method as describedforN-((6-(3-chloro-4-fluorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine:

EXAMPLE 25

N-((6-(3-Fluorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine.M/Z=401.2 [M+H], calc 401.4153 for C₂₂H₁₇FN₆O.

EXAMPLE 26

7-Methoxy-N-((6-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-1,5-naphthyridin-4-amine.M/Z=383.2 [M+H], calc 382.4252 for C₂₂H₁₈N₆O.

5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thiophene-2-carbonylchloride: To a suspension of5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thiophene-2-carboxylicacid (prepared according to general method A) (0.500 g, 1.15 mmol) indichloromethane at 0° C. was added thionyl chloride (1.26 ml, 17.3 mmol)dropwise. Three drops DMF were added and the solution was stirred atroom temp for three hours. The solution was concentrated to a brownresidue and taken forward without further purification.

EXAMPLE 27

(5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thiophen-2-yl)(morpholino)methanone:To a solution of5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thiophene-2-carbonylchloride (0.260 g, 0.58 mmol) in dichloromethane (5 mL) was addedN-ethyl-N-isopropylpropan-2-amine (0.15 ml, 0.86 mmol) and morpholine(0.15 ml, 1.7 mmol). The solution was stirred at room temperature fortwo hours then was concentrated in vacuo. The brown residue was purifiedvia MPLC chromatography (eluted with 0-5% methanol in dichloromethane)to yield the product as a tan solid. MS m/z=503.0 [M+1]⁺. Calc'd forC₂₅H₂₂N₆O₄S: 502.1.

EXAMPLE 28

(5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thiophen-2-yl)(pyrrolidin-1-yl)methanone:Prepared by a method similar to(5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thiophen-2-yl)(morpholino)methanone.MS m/z=487.1 [M+1]⁺. Calc'd for C₂₅H₂₂N₆O₃S: 486.2

EXAMPLE 29

5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-N,N-dimethylthiophene-2-carboxamide:To a solution of5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thiophene-2-carbonylchloride (0.260 g, 0.58 mmol) in dichloromethane was addedN-ethyl-N-isopropylpropan-2-amine (0.20 ml, 1.2 mmol) and dimethylamine(1.4 ml, 2.9 mmol). The solution was stirred at room temperature for onehour then was concentrated in vacuo. The residue was triturated withwater and filtered; the resulting precipitate was triturated withacetonitrile and filtered to yield the product as an off-white solid. MSm/z=461.0 [M+1]⁺. Calc'd for C₂₃H₂₀N₆O₃S: 460.1.

EXAMPLE 30

5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-N-methylthiophene-2-carboxamide:Prepared by a method similar to(5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thiophen-2-yl)(morpholino)methanone.MS m/z=447.0 [M+1]⁺. Calc'd for C₂₂H₁₈N₆O₃S: 446.1

EXAMPLE 31

5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thiophene-2-carboxamide:Prepared by a method similar to(5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thiophen-2-yl)(morpholino)methanone.MS m/z=433.0 [M+1]⁺. Calc'd for C₂₁H₁₆N₆O₃S: 432.1.

5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-3-methylthiophene-2-carbonylchloride: To a suspension of5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-3-methylthiophene-2-carboxylicacid (prepared by General Method A)(0.150 g, 0.335 mmol) indichloromethane (2 mL) was added thionyl chloride (0.734 ml, 10.1 mmoland DMF (1 drop). The solution was stirred at room temp for three hoursthen concentrated and taken forward without further purification.

EXAMPLE 32

(5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-3-methylthiophen-2-yl)(morpholino)methanone:To a solution of5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-3-methylthiophene-2-carbonylchloride (0.100 g, 0.21 mmol) in dichloromethane (2 mL) at 0° C. wasadded morpholine (0.19 g, 2.1 mmol). The solution was stirred at roomtemperature twenty minutes, then was concentrated and purified by MPLCchromatography (eluted with 3% methanol in dichloromethane) to yield ayellow solid. Trituration in acetonitrile and filtration afforded theproduct as a white solid. MS m/z=517.2 [M+1]⁺. Calc'd for C₂₆H₂₄N₆O₄S:516.2.

7-methoxy-N-((6-(2-(triethylsilyl)ethynyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine:To an argon flushed pressure vial (15 mL) was added copper (I)iodide(0.0070 g, 0.037 mmol), PdCl₂(dppf)-CH₂Cl₂ Adduct (0.012 g, 0.015 mmol),N-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine(0.050 g, 0.15 mmol), and triethyl(ethynyl)silane (0.13 ml, 0.73 mmol)in acetonitrile (2 mL) followed by triethylamine (0.61 ml, 4.4 mmol).The vial was sealed and stirred at room temperature overnight Thesolution was concentrated and purified by MPLC (eluted with 0-10%(90:10:1 DCM:MeOH:NH₄OH)) to yield the product as a light yellow solid.MS m/z=446.1 [M+1]⁺. Calc'd for C₂₃H₂₇N₇OSi: 445.2.

EXAMPLE 33

N-((6-ethynyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine:To a solution of7-methoxy-N-((6-(2-(triethylsilyl)ethynyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine(0.360 g, 0.808 mmol) in acetic acid (8 mL) was added TBAF (1.21 ml,1.21 mmol). The mixture was stirred at room temperature overnight,additional TBAF (1.21 ml, 1.21 mmol) was added and the mixture washeated to 50° C. for five hours. The mixture was concentrated andpurified via MPLC (eluted with 0-10% (1:10:90 NH₄OH:MeOH:DCM) indichloromethane) to yield the product as an off-white solid. MSm/z=332.0 [M+1]⁺. Calc'd for C₁₇H₁₃N₇O: 331.1.

tert-butyl(6-(2-(triethylsilyl)ethynyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate:A 1 L-round-bottomed flask flushed with argon was charged withtert-butyl(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (12.00 g,42.3 mmol), Pd(dppf)Cl₂—CH₂Cl₂ adduct (3.45 g, 4.23 mmol), copper iodide(2.01 g, 10.6 mmol) at room temperature. Acetonitrile (400 mL) was addedfollowed by triethyl(ethynyl)silane (37.9 ml, 211 mmol). Upon stirringthe reaction mixture turned dark red. Triethylamine (177 ml, 1269 mmol)was added via cannula over five minutes. The first drops resulted in achange of color to light yellow/orange. At the end of the addition, thereaction mixture was dark red again. After stirring at 50° C. for onehour, the mixture was cooled to room temperature and concentrated invacuo. Purification by MPLC (ISCO, EtOAc/MeOH: 100/0 to 90/10) affordedthe desired product. The material was taken forward without furtherpurification. MS m/z=388.3 [M+1]⁺. Calc'd for C₁₉H₂₉N₅O₂Si: 387.2.

tert-butyl(6-ethynyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate:Potassium fluoride (2M in water, 27.6 ml, 55.3 mmol) was added to astirred suspension oftert-butyl6-(2-(triethylsilyl)ethynyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate(3.57 g, 9.21 mmol) in acetonitrile (56 mL) at room temperature. Thereaction mixture turned dark immediately, and was stirred at room tempfor twenty minutes until complete. The mixture was concentrated invacuo, triturated with water and filtered to yield the product as abrown solid (2.46 g). MS m/z=274.1 [M+1]⁺. Calc'd for C₁₃H₁₅N₅O₂: 273.1.

tert-butyl(6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate:To a solution of nitroethane (1.02 ml, 14.3 mmol) in benzene (50 mL) wasadded phenyl isocyanate (3.12 ml, 28.5 mmol). The mixture was stirred at50° C. for twenty minutes followed by the addition of tert-butyl(6-ethynyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (3.00 g,11.0 mmol) and triethylamine (0.0765 ml, 0.549 mmol). The mixture wasstirred at 50° C. for six hours then at room temperature overnight. Themixture was cooled to room temperature, filtered and the resulting brownprecipitate was washed with additional benzene. The filtrate wasconcentrated to yield the product as a black solid. MS m/z=331.1 [M+1]⁺.Calc'd for C₁₅H₁₈N₆O₃: 330.1.

(6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanamine:To a solution of tert-butyl(6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate(3.63 g, 11.0 mmol) in dichloromethane (50 mL) was added trifluoroaceticacid (16.9 ml, 220 mmol) and the mixture was stirred at room temperaturefor one hour. The mixture was concentrated, taken up in a solution ofammonia in methanol (2.0 M) and purified by MPLC chromatography (elutedwith 0-10% (1:10:90 NH₄OH:MeOH:DCM) in DCM) to yield the product as abrown solid. MS m/z=230.8 [M+1]⁺. Calc'd for C₁₀H₁₀N₆O: 230.1.

EXAMPLE 34

7-methoxy-N-((6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine:To a microwave vial (10-20 mL) was added(6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanamine(1.00 g, 4.34 mmol) and 8-chloro-3-methoxy-1,5-naphthyridine (1.10 g,5.65 mmol) in 2-butanol (12 mL). The suspension was stirred at 120° C.under microwave irradiation for four hours. The mixture was concentratedand taken up in ammonia in methanol (2.0 M) then purified by MPLCchromatography (eluted with 0-10% methanol in dichloromethane) to yieldthe product as a tan solid. MS m/z=389.0 [M+1]⁺. Calc'd for C₁₉H₁₆N₈O₂:388.1

EXAMPLE 35

Ethyl-5-(3-((7-methoxy-1,5-naphthyridin-4-ylamino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)isoxazole-3-carboxylate:Prepared by a method similar to7-methoxy-N-((6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine.MS m/z=446.6 [M+1]⁺. Calc'd for C₂₁H₁₈N₈O₄: 446.2.

EXAMPLE 36

5-(3-((7-methoxy-1,5-naphthyridin-4-ylamino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)isoxazole-3-carboxylicacid: To a solution of ethyl5-(3-((7-methoxy-1,5-naphthyridin-4-ylamino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)isoxazole-3-carboxylate(0.045 g, 0.10 mmol) in methanol (1 mL) and water (0.5 mL) was addedsodium hydroxide (6M, 0.050 ml, 0.30 mmol). The mixture was stirred at50° C. for two hours, then was concentrated and diluted with water (2mL). 2M HCL was added dropwise until precipitation was observed, the tansolid was collected by filtration. The solid was taken up in isopropanoland heated to 100° C. The resulting suspension was cooled to roomtemperature and filtered to yield the product as a tan solid. MSm/z=418.6 [M+1]⁺. Calc'd for C₁₉H₁₄N₈O₄: 418.1.

tert-butyl-(6-(3-((tetrahydro-2H-pyran-2-yloxy)methyl)isoxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate:Prepared by a method similar totert-butyl-(6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate.MS m/z=430.7 [M+1]⁺. Calc'd for C₂₀H₂₆N₆O₅: 430.2.

(5-(3-(aminomethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)isoxazol-3-yl)methanol:To a solution of tert-butyl(6-(3-((tetrahydro-2H-pyran-2-yloxy)methyl)isoxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate(4.73 g, 11.0 mmol) in dichloromethane (50 mL) was added trifluoroaceticacid (16.9 ml, 220 mmol). The mixture was stirred at room temperaturefor one hour, then was concentrated, taken up in 2.0 M ammonia inmethanol and purified by MPLC chromatography (eluted with 0-10% (1:10:90NH₄OH:MeOH:DCM) in DCM) to yield the product as a tan solid. MSm/z=246.9 [M+1]⁺. Calc'd for C₁₀H₁₀N₆O₂: 246.1.

EXAMPLE 37

(5-(3-((7-methoxy-1,5-naphthyridin-4-ylamino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)isoxazol-3-yl)methanol:Prepared by a method similar to7-methoxy-N-((6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine.MS m/z=404.6 [M+1]⁺. Calc'd for C₁₉H₁₆N₈O₃: 404.1.

5-(tributylstannyl)-2-(trimethylsilyl)thiazole: To a stirred solution ofbutyllithium (0.763 ml, 1.91 mmol) in diethyl ether (10 mL) at −78° C.was added dropwise over 30 minutes a solution of2-(trimethylsilyl)thiazole (0.300 ml, 1.91 mmol) in ether (5 mL). Thesolution was stirred at −78° C. for one hour, followed by the additionof chlorotrimethylstannane (1.59 ml, 1.59 mmol) in THF over 15 minutes.After an additional hour at −78° C., the solution was washed withsaturated bicarbonate and extracted with diethyl ether. Organic extractswere dried over magnesium sulfate and filtered then concentrated invacuo to yield the product as a colorless oil.

5-(tributylstannyl)thiazole: To a solution of2-(trimethylsilyl)-5-(trimethylstannyl)thiazole (0.509 g, 1.6 mmol) in 5mL THF was added 2 N HCl (1.0 mL). The solution was stirred at roomtemperature for one hour. The solution was diluted with diethyl etherand washed with sodium bicarbonate. Organic extracts were dried overmagnesium sulfate and filtered then concentrated to yield the product asa colorless oil.

3-methyl-5-(tributylstannyl)isoxazole: To a solution of nitroethane(0.0952 ml, 1.33 mmol) in benzene (2 mL) was added phenyl isocyanate(0.291 ml, 2.66 mmol). The solution was stirred at 50° C. for tenminutes followed by the addition of triethylamine (0.00925 ml, 0.0666mmol) and tributyl(ethynyl)stannane (0.365 ml, 1.27 mmol). The mixturewas left to stir at 50° C. overnight. The solution was diluted withwater and filtered though a celite plug, the resulting filtrate wasextracted with toluene. Organic extracts were dried over magnesiumsulfate and filtered then concentrated to yield the product as a yellowoil.

EXAMPLE 38

In a pressure vessel, 3N HCl (1.2 ml, 3.5 mmol) was added to4-((6-(6-fluoropyridin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-methoxyquinoline(0.071 g, 0.18 mmol) in dioxane (0.60 mL). The reaction mixture was thenheated at 100° C. for 3.5 h. Concentrated HCl (0.300 mL, 9.9 mmol) wasadded and the reaction was heated at 100° C. for 2 h. The reactionmixture was concentrated in vacuo, and then dried on high vacuum.Triethylamine (0.74 ml, 5.3 mmol) was added to the compound, and it wasallowed to stir for one hour until the free base crashed out ofsolution. The compound was dissolved partially in DCM/MeOH, however,fully dissolved after addition of hot DMSO. The compound was purifiedvia flash chromatograph, eluting with 0-10% MeOH/NH₄OH in DCM. Thecompound was sonicated in DCM and filtered to remove thetriethylamine-hydrochloride salt, and yielded6-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)pyridin-2(1H)-one.

EXAMPLE 39

6-((6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline Amixture of 1-(6-chloropyridazin-3-yl)hydrazine (1.67 g, 12 mmol),2-(quinolin-6-yl)acetic acid (1.65 g, 8.8 mmol), and HCl (2000 μl, 24mmol) was heated in an oil bath at 110° C. for 20 min before it washeated in a microwave (Personal Chemistry) at 180° C.&15 min. Themixture was quenched with a solution of NaOH (1.2 g, 5 mL) slowly untilthe suspension is ˜neutral in pH. The mixture was filtered and washedwith H₂O (2×5 mL). A brown solid was obtained (2.2 g). The solid wastreated with aqueous Na₂CO₃ (3 g, 20 mL, pH ˜11) and heated at 50° C.for 30 min. The blue mixture was cooled to room temperature, andfiltered. The black solid was washed with H₂O and lyophilized to givethe product.

LCMS: calc'd for C₁₅H₁₀ClN₅: 295.1. found 296.1 (M+1).

EXAMPLE 403-Methoxy-6-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline

A mixture of tert-butyl 2-(3-methoxyquinolin-6-yl)acetate (148 mg) and1-(6-phenylpyridazin-3-yl)hydrazine (126 mg) in HCl (conc., 0.3 mL) washeated at 100° C. for 5 min and was subject to microwave heating (180°C., 15 min). The yellow sludge was quenched with NaOH(SN, 1 mL). Thepink mixture was filtered and washed with NaOH (1 N, 1 mL), H₂O (2 mL).The solid was suspended in DMF (2 mL)-DCM (2 mL). MeI (0.2 mL) was addedfollowed by the addition of NaOH (2N, 1 mL). After 2 h, the mixture waspartitioned between DCM (10 mL) and aqueous Na₂SO₃ (5 mL). The organicwas dried over MgSO₄, concentrated, and purified in silica (1-15% MeOHin DCM) to give the product as a yellow powder.

LCMS: calc'd for C₂₂H₁₇N₅O: 367.1. found 368.2 (M+1).

EXAMPLE 414-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2-methylbut-3-yn-2-ol 1)6-bromoH-imidazo[1,2-a]pyridine-3-carbaldehyde

A 250 mL RB flask was charged with DMF (21.3 ml, 274 mmol) and cooled to0° C.; phosphorus oxychloride (2.46 ml, 26.4 mmol) was added dropwise.This was stirred for 1 hour, then 6-bromoH-imidazo[1,2-a]pyridine (2.00g, 10.2 mmol) was added in one portion. This was stirred at 100° C. for5 hours and at room temperature for 16 hours. The flask was cooled to 0°C. and slowly neutralized with 6N aq. NaOH and sat. aq. NaHCO₃,resulting in the formation of a precipitate which was collected byfiltration to give 6-bromoH-imidazo[1,2-a]pyridine-3-carbaldehyde as ayellow-orange solid.

2) (6-bromoH-imidazo[1,2-a]pyridin-3-yl)methanol

A 50 mL RB flask was charged with sodium borohydride (0.074 g, 2.0 mmol)and water (0.84 ml, 47 mmol), then cooled to 0° C. A solution of6-bromoH-imidazo[1,2-a]pyridine-3-carbaldehyde (0.8792 g, 3.9 mmol),methanol (6.3 ml, 156 mmol), and DCM was added slowly. This was allowedto warm to room temperature. The mixture was concentrated, then theyellow residue was triturated with water and filtered to give(6-bromoH-imidazo[1,2-a]pyridin-3-yl)methanol as a yellow solid.

3) 4-((6-bromoH-imidazo[1,2-a]pyridin-3-yl)methoxy)-7-methoxyquinoline

A 10-20 mL microwave vial was charged with(6-bromoH-imidazo[1,2-a]pyridin-3-yl)methanol (0.756 g, 3.3 mmol),4-chloro-7-methoxyquinoline (0.81 g, 4.2 mmol), cesium carbonate (2.2 g,6.7 mmol), and DMSO (8.00 ml, 113 mmol), sealed, and placed in aPersonal Chemistry microwave at 100° C. for 2 hours. The reactionmixture was added dropwise to a flask containing water, resulting in theformation of a precipitate which was collected by filtration. The solidwas dissolved in a combination of MeOH/DCM and filtered. The filtratewas concentrated and triturated with EtOAc/DCM. The solid was dissolvedin a small amount of hot MeOH and DCM and purified by chromatographyusing a 40 g ISCO column, eluting with a gradient of 1-7% MeOH (with 10%NH₄OH)/DCM over 40 minutes.

4)4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2-methylbut-3-yn-2-ol

A 16 mm test tube was charged with4-((6-bromoH-imidazo[1,2-a]pyridin-3-yl)methoxy)-7-methoxyquinoline(0.0607 g, 0.16 mmol), phenylboronic acid (0.039 g, 0.32 mmol), SPhos(0.0065 g, 0.016 mmol), Potassium phosphate (0.10 g, 0.47 mmol),Pd2(dba)3 (0.0036 g, 0.0039 mmol), and 1-butanol (0.014 ml, 0.16 mmol),then stirred at 100° C. for 16 hours. The reaction mixture was dilutedwith chloroform (15 mL) and washed with water (15 mL), sat. aq. NaHCO₃(15 mL), and brine (15 mL); the organic layer was dried with MgSO₄,filtered, and concentrated. This was purified using the prep HPLCmachine using a gradient of 10% MeCN/water to 95% MeCN/water over 20min. The fractions were combined and the product free based by dilutingwith 10% MeOH/HCCl₃ (30 mL) and washing with sat. aq. NaHCO₃ (30 mL).The organic layer was dried with MgSO₄, filtered, and concentrated, thenthe resulting yellow solid was submitted to the Analytical Chemistrygroup for purification. This was returned as the formic acid salt inwater, which was concentrated, free based with sat. NaHCO₃ (5 mL),diluted with water (15 mL), and extracted with 10% MeOH/HCCl₃ (3×25 mL).The combined organics were dried with MgSO₄, filtered, and concentratedto yield7-methoxy-4-((6-phenylH-imidazo[1,2-a]pyridin-3-yl)methoxy)quinoline. MS(ESI pos. ion) m/z: 382 (MH+). Calc'd exact mass for C₂₄H₁₉N₃O₂: 381.

EXAMPLE 42N-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7H-purin-6-amine

A 15 mL tube was charged with(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanamine (0.100 g,0.444 mmol), 6-chloropurine (0.103 g, 0.666 mmol), and sec-butanol (3.00ml, 32.4 mmol), sealed, then heated in a 100° C. oil bath for 5 hours.The reaction mixture was concentrated and the yellow residue waspurified by MPLC using a 40 g RediSep column, eluting with a gradient of3-8% MeOH/DCM over 80 minutes.N-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7H-purin-6-amine(0.0500 g, 32.8% yield) was isolated as the hydrochloride salt.

MS (ESI pos. ion) m/z: 344 (MH+). Calc'd exact mass for C₂₃H₁₈FN₅O₂:343.

EXAMPLE 435-(3-((7-methoxy(quinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-N,N-dimethylpyridin-2-amine

A 48 mL tube was charged with 6-(dimethylamino)pyridin-3-ylboronic acid(0.109 g, 0.658 mmol),4-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline(0.150 g, 0.439 mmol), and DMF (3.00 ml, 38.6 mmol), and stirred for 10minutes. A solution of potassium carbonate (0.182 g, 1.32 mmol) andwater (0.696 ml, 38.6 mmol) was added, followed byPdCl2(dppf)-CH2Cl2Adduct (0.0358 g, 0.0439 mmol). The tube was flushedwith argon, sealed, and heated in a 80° C. oil bath for 5 hours. Themixture was concentrated, and the residue was triturated with water togive a brown solid which was purified by MPLC using a 40 g column,eluting with 1-5% MeOH/DCM over 40 minutes to give5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-N,N-dimethylpyridin-2-amineas a dark green solid.

MS (ESI pos. ion) m/z: 428 (MH+). Calc'd exact mass for C₂₃H₁₈FN₅O₂:427.

EXAMPLE 447-methoxy-4-((6-(6-morpholinopyridin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)quinoline

Prepared in a similar manner as5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-N,N-dimethylpyridin-2-amine.

MS (ESI pos. ion) m/z: 470 (MH+). Calc'd exact mass for C₂₃H₁₈FN₅O₂:469.

EXAMPLE 454-((6-(H-imidazo[1,2-a]pyridin-6-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline

Prepared in a similar manner as5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-N,N-dimethylpyridin-2-amine.

MS (ESI pos. ion) m/z: 424 (MH+). Calc'd exact mass for C₂₃H₁₇N₇O₂: 423.

EXAMPLE 46 tert-butyl4-(5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyridin-2-yl)piperazine-1-carboxylate.

Prepared in a similar manner as5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-N,N-dimethylpyridin-2-amine.

MS (ESI pos. ion) m/z: 569 (MH+). Calc'd exact mass for C₃₀H₃₂N₈O₄: 568.

EXAMPLE 477-methoxy-4-((6-(6-(piperazin-1-yl)pyridin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)quinoline

A 50 mL recovery flask was charged with tert-butyl4-(5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyridin-2-yl)piperazine-1-carboxylate(0.250 g, 0.44 mmol), TFA (0.75 ml, 9.6 mmol), and DCM (1.50 ml, 23mmol), then stirred at room temperature for 1.5 hours. The reactionmixture was concentrated, then quenched with sat. aq. NaHCO₃. Themixture was diluted with DCM (60 mL), resulting in an emulsion. Theemulsion was filtered to give a brown solid. The solid was trituratedwith a combination of DCM/MeOH/MeCN and filtered to give7-methoxy-4-((6-(6-(piperazin-1-yl)pyridin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)quinoline.

MS (ESI pos. ion) m/z: 469 (MH+). Calc'd exact mass for C₂₅H₂₄N₈O₂: 468.

EXAMPLE 48 tert-butyl3-(5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyridin-2-ylamino)pyrrolidine-1-carboxylate 1)4-((6-(6-fluoropyridin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline

Prepared in a similar manner as5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-N,N-dimethylpyridin-2-amine.

2) tert-butyl3-(5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyridin-2-ylamino)pyrrolidine-1-carboxylate

A 0.5-2 mL microwave vial was charged with4-((6-(6-fluoropyridin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline(0.100 g, 0.249 mmol), tert-butyl 3-aminopyrrolidine-1-carboxylate(0.116 g, 0.622 mmol), and DMSO (4.00 ml, 56.4 mmol), sealed and placedin a Personal Chemistry microwave for 1 hour at 100° C. and then 30minutes at 120° C. Water was added slowly to the reaction mixture untila precipitate formed. The solid was collected and purified by MPLC usinga 40 g RediSep column, eluting with a gradient of 3-6% MeOH/DCM over 40minutes. The solid was triturated with MeCN and filtered; the motherliquor was concentrated to give tert-butyl3-(5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyridin-2-ylamino)pyrrolidine-1-carboxylate.

MS (ESI pos. ion) m/z: 569 (MH+). Calc'd exact mass for C₃₀H₃₂N₈O₄: 568.

EXAMPLE 495-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-N-(pyrrolidin-3-yl)pyridin-2-amine

Prepared in a similar manner as7-methoxy-4-((6-(6-(piperazin-1-yl)pyridin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)quinoline.

MS (ESI pos. ion) m/z: 469 (MH+). Calc'd exact mass for C₂₅H₂₄N₈O₂: 468.

EXAMPLE 504-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2-methylbut-3-yn-2-ol

A 25×200 mm test tube was charged with4-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline(0.150 g, 0.439 mmol), 2-methylbut-3-yn-2-ol (0.213 ml, 2.19 mmol),copper (I) iodide (0.0209 g, 0.110 mmol), triethylamine (1.83 ml, 13.2mmol), and acetonitrile (5.00 ml, 96.2 mmol), flushed with argon,sealed, and placed in a 90° C. oil bath for 30 minutes.PdCl2(dppf)-CH2Cl2Adduct (0.0358 g, 0.0439 mmol) was added in oneportion, the tube flushed with argon, sealed, then heated in a 90° C.oil bath for 4 hours.

The reaction mixture was filtered thru a pad of silica gel (eluting withEtOAc/DCM/MeOH), then concentrated to yield a dark brown oil. This waspurified by MPLC, using a 40 g RediSep column, eluting with 1-7%MeOH/DCM over 40 minutes. The appropriate fractions were collected togive4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2-methylbut-3-yn-2-ol(0.0877 g, 51.3% yield).

MS (ESI pos. ion) m/z: 390 (MH+). Calc'd exact mass for C₂₁H₁₉N₅O₃: 389.

EXAMPLE 511-(2-fluoro-4-(3-((7-methoxy-1,5-naphthyridin-4-ylamino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)pyrrolidin-2-one 1)1-(4-chloro-2-fluorophenyl)pyrrolidin-2-one

A 100 mL sealed tube was charged with 4-chloro-2-fluoro-1-iodobenzene(0.498 ml, 3.90 mmol), pyrrolidin-2-one (0.598 ml, 7.80 mmol),(1R,2R)-cyclohexane-1,2-diamine (0.0703 ml, 0.585 mmol), potassiumphosphate (1.66 g, 7.80 mmol), copper (I) iodide (0.0223 g, 0.117 mmol),and 1,4-dioxane (4.00 ml, 46.8 mmol), then flushed with argon, sealed,and placed in a 110° C. oil bath for 17 hours. The reaction mixture wasfiltered through a pad of silica gel, eluting with EtOAc and DCM, thenthe filtrate was concentrated to yield a brown oil This was purified bycolumn chromatography using a 40 g ISCO column, eluting with a gradientof 3-5% MeOH/DCM over 30 minutes to give1-(4-chloro-2-fluorophenyl)pyrrolidin-2-one (0.903 g, 108% yield) as ayellow solid.

2)1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one

A 48 mL sealed tube was charged with1-(4-chloro-2-fluorophenyl)pyrrolidin-2-one (0.444 g, 2.08 mmol),pinacol diborane (1.06 g, 4.16 mmol), X-Phos (0.0991 g, 0.208 mmol), Pd2dba3 (0.0571 g, 0.0623 mmol), potassium acetate (0.408 g, 4.16 mmol),and 1,4-dioxane (4.62 ml, 54.0 mmol), flushed with argon, sealed, thenplaced in a 90° C. oil bath for 5 hours. The reaction mixture wasdiluted with EtOAc (100 mL) and washed with water (100 mL), sat. NaHCO₃(100 mL), and brine (100 mL), dried with MgSO₄, filtered, andconcentrated. This was purified by MPLC using a 40 g RediSep column,eluting with 1-5% MeOH/DCM over 40 minutes. The fractions wereconcentrated to give1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one,˜85% pure, as an orange oil that solidified upon standing.

3) tert-butyl(6-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate

A 48 mL sealed tube was charged with tert-butyl(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (0.150 g,0.529 mmol),1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one(0.242 g, 0.793 mmol), PdCl2(dppf)-CH2Cl2Adduct (0.0432 g, 0.0529 mmol),cesium carbonate (0.689 g, 2.11 mmol), 1,4-dioxane (3.62 ml, 42.3 mmol),and water (0.905 ml, 50.2 mmol), flushed with argon, sealed, then placedin a 80° C. oil bath for 5 hours. The contents were transferred to aflask and concentrated. The solid was triturated with water to give ared residue, which was purified by MPLC using a 40 g RediSep column,eluting with 2-6% MeOH/DCM over 40 minutes. tert-butyl(6-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate(0.117 g, 51.9% yield) was isolated as a tan solid.

4)1-(4-(3-(aminomethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2-fluorophenyl)pyrrolidin-2-one

A 50 mL recovery flask was charged with tert-butyl(6-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate(0.117 g, 0.274 mmol), TFA (0.0211 ml, 0.274 mmol), and DCM (0.0177 ml,0.274 mmol), then stirred open to air at room temperature for 2 hours.The mixture was concentrated, then taken up in MeOH. K₂CO₃ was added,and this was stirred for 1 hour. The mixture was concentrated, then theresidue was taken up in MeOH/CHCl₃ then filtered. The filtrate wasevaporated, taken up in water, then passed through a reverse phase C18column, eluting with MeOH/DCM, then concentrated.

5)1-(2-fluoro-4-(3-((7-methoxy-1,5-naphthyridin-4-ylamino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)pyrrolidin-2-one

A 0.5-2 mL microwave vial was charged with1-(4-(3-(aminomethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2-fluorophenyl)pyrrolidin-2-one(0.0792 g, 0.243 mmol), 8-chloro-3-methoxy-1,5-naphthyridine (0.0590 g,0.303 mmol), and butan-2-ol (1.00 ml, 0.243 mmol), sealed, then placedin a Personal Chemistry Microwave for 4 hours at 120° C. The mixture wasconcentrated, then triturated with MeOH to give1-(2-fluoro-4-(3-((7-methoxy-1,5-naphthyridin-4-ylamino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)pyrrolidin-2-oneas the hydrochloric salt.

MS (ESI pos. ion) m/z: 485 (MH+). Calc'd exact mass for C₂₅H₂₁FN₈O₂:484.

EXAMPLE 525-(3-((7-methoxy-1,5-naphthyridin-4-ylamino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2-methylisoindolin-1-one 1)4-bromo-2-(hydroxymethyl)-N-methylbenzamide

A 500 mL RB flask was charged with aluminum(III) chloride (4.1 g, 31mmol) and 10 mL of 1,2-dichloroethane (99 ml, 1142 mmol), then cooled to0° C. A separate 250 mL flask was charged with 90 mL of1,2-dichloroethane (90 ml, 1142 mmol) and cooled to 0° C.; methylamine(gas) (1.8 g, 59 mmol) was bubbled through the solution for 10 minutes.The dichloroethane solution was slowly poured into the aluminum chloridesolution, resulting in the formation of a thick white slush. This waswarmed to room temperature. 5-bromoisobenzofuran-1(3H)-one (5.00 g, 23mmol) was added in one portion and the reaction mixture was stirred for2.5 hours and quenched with water. The mixture was filtered to removethe solid impurities, then the filtrate was washed with 0.5N aqueous HCl(100 mL) and brine (200 mL). The organic layer was dried with MgSO₄,filtered, and concentrated to give a white solid. This was trituratedwith EtOAc and filtered to give4-bromo-2-(hydroxymethyl)-N-methylbenzamide (3.34 g, 58% yield) as awhite solid.

2) 5-bromo-2-methylisoindolin-1-one

A 150 mL sealed tube was charged with4-bromo-2-(hydroxymethyl)-N-methylbenzamide (3.34 g, 13.7 mmol) and1,3-dimethylimidazolidin-2-one (40.4 ml, 369 mmol). The solution wascooled to 0° C. and Isopropylmagnesium chloride (15.3 ml, 30.5 mmol) wasadded slowly. The tube was capped and the reaction mixture was stirredat room temperature for 30 minutes. This was recooled to 0° C. andN,N,N,N-tetramethylphosphorodiamidoyl chloride (2.64 ml, 17.8 mmol) wasadded in one portion; this mixture was stirred at room temperature for 4hours. The tube was placed in a 150° C. oil bath for 1 hour. The mixturewas then diluted with EtOAc (100 mL), then washed with 1M aqueous HCl.The aqueous layer was extracted with ethyl acetate (3×100 mL) and thenthe combined organics were washed with water (100 mL) and brine (100mL), dried with MgSO₄, filtered, then concentrated to give a yellow oil.This was purified by column chromatography, eluting with 1-4% MeOH/DCMto give 5-bromo-2-methylisoindolin-1-one (1.774 g, 57.3% yield) as ayellow solid.

3)2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one

Prepared in a similar manner as1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one.

4) tert-butyl(6-(2-methyl-1-oxoisoindolin-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate

Prepared in a similar manner as tert-butyl(6-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate.

5)5-(3-(aminomethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2-methylisoindolin-1-one

Prepared in a similar manner as1-(4-(3-(aminomethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2-fluorophenyl)pyrrolidin-2-one.

6)5-(3-((7-methoxy-1,5-naphthyridin-4-ylamino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2-methylisoindolin-1-one

Prepared in a similar manner as1-(2-fluoro-4-(3-((7-methoxy-1,5-naphthyridin-4-ylamino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)pyrrolidin-2-one.

MS (ESI pos. ion) m/z: 453 (MH+). Calc'd exact mass for C₂₄H₂₀N₈O₂: 452.

EXAMPLE 53N-((6-(1-isopropyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine 1)tert-butyl(6-(1-isopropyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate

Prepared in a similar manner as tert-butyl(6-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate.

2)(6-(1-isopropyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanaminehydrochloride

Prepared in a similar manner as1-(4-(3-(aminomethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2-fluorophenyl)pyrrolidin-2-one.

3)N-((6-(1-isopropyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine

Prepared in a similar manner as1-(2-fluoro-4-(3-((7-methoxy-1,5-naphthyridin-4-ylamino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)pyrrolidin-2-one.

MS (ESI pos. ion) m/z: 416 (MH+). Calc'd exact mass for C₂₁H₂₁N₉O₂: 415.

EXAMPLE 54N-((6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine

A 48 mL sealed tube was charged withN-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine(0.150 g, 0.439 mmol), 1H-pyrazol-4-ylboronic acid (0.0737 g, 0.658mmol), and DMF (3.00 ml, 38.6 mmol). A solution of potassium carbonate(0.182 g, 1.32 mmol) and water (0.696 ml, 38.6 mmol) was added, followedby PdCl2(dppf)-CH2Cl2Adduct (0.0358 g, 0.0439 mmol). The tube wasflushed with argon, sealed, then placed in a 90° C. oil bath for 5hours. The mixture was concentrated and the black solid was trituratedwith water to remove K₂CO₃, then purified by column chromatography usinga 40 g RediSep column, eluting with 30-70% (90:10:1 DCM:MeOH:NH₄OHsolution) in DCM over 40 minutes. Pure fractions were collected to giveN-((6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amineas a white solid.

MS (ESI pos. ion) m/z: 374 (MH+). Calc'd exact mass for C₁₈H₁₅N₉O: 373.

EXAMPLE 557-methoxy-N-((6-phenyl-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl)methyl)-1,5-naphthyridin-4-amine 1)3-(azidomethyl)-6-phenyl-[1,2,4]triazolo[4,3-b][1,2,4]triazine

A 16 mm test tube was charged with.(6-phenyl-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl)methanol (0.500 g,2.20 mmol), Reactant 2 (0.951 ml, 4.40 mmol), DBU (0.663 ml, 4.40 mmol),and toluene (8.16 ml, 77.0 mmol), flushed with argon, sealed, thenstirred at room temperature for 3 hours. The dark maroon mixture wasconcentrated and the resulting dark purple/black oil was purified bycolumn chromatography using a gradient of 3-5% MeOH/DCM over 20 minutes.3-(azidomethyl)-6-phenyl-[1,2,4]triazolo[4,3-b][1,2,4]triazine wasisolated as a brown solid.

2) (6-phenyl-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl)methanamine

A 50 mL RB flask was charged with3-(azidomethyl)-6-phenyl-[1,2,4]triazolo[4,3-b][1,2,4]triazine (0.3492g, 1.38 mmol) and THF (14.0 ml, 171 mmol), resulting in a dark brownsolution. Triphenylphosphine (0.545 g, 2.08 mmol) and water (0.0998 ml,5.54 mmol) were added, and the flask was placed in a 65° C. oil bath for2 hours. The reaction mixture was concentrated to give a thick brownoil, which was purified by column chromatography using an 80 g ISCOcolumn, eluting with a gradient of 5% MeOH (containing NH₄OH)/DCM to 10%MeOH (containing NH₄OH)/DCM over 40 minutes.(6-phenyl-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl)methanamine wasisolated as a yellow solid.

3)7-methoxy-N-((6-phenyl-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl)methyl)-1,5-naphthyridin-4-amine

Prepared in a similar manner as1-(2-fluoro-4-(3-((7-methoxy-1,5-naphthyridin-4-ylamino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)pyrrolidin-2-one.

MS (ESI pos. ion) m/z: 385 (MH+). Calc'd exact mass for C₂₀H₁₆N₈O: 384.

EXAMPLE 56 (6-Phenylimidazo[1,2-b]pyridazin-3-yl)methanol

To a mixture of (6-chloroimidazo[1,2-b]pyridazin-3-yl)methanol (seeGaltier, C. et al, Antiviral Chemistry & Chemotherapy, 2003, 14,177-182) (0.200 g, 1.09 mmol), phenylboronic acid (0.133 g, 1.09 mmol),PdCl₂(dppf)-CH₂Cl₂ (0.0445 g, 0.0545 mmol) in dioxane was added satNaHCO₃ (1.20 ml, >2.40 mmol). The mixture was blanketed with N₂, thevessel sealed and heated at 80 C for 1 h. The mixture was allowed tocool to rt and diluted with EtOAc. The organic phase was washed withwater, then sat. NaHCO₃, dried over Na₂SO₄, filtered and evaporated. Themixture was purified via flash chromatography using a gradient of 0% to10% MeOH in EtOAc. The title compound was collected as a white solid.

The following compounds were prepared according to the method describedfor (6-phenylimidazo[1,2-b]pyridazin-3-yl)methanol:

-   (6-(3-Fluorophenyl)imidazo[1,2-b]pyridazin-3-yl)methanol-   (6-(3,4-Difluorophenyl)imidazo[1,2-b]pyridazin-3-yl)methanol-   (6-(3,4,5-Trifluorophenyl)imidazo[1,2-b]pyridazin-3-yl)methanol

7-Methoxy-4-((6-phenylimidazo[1,2-b]pyridazin-3-yl)methoxy)quinoline. Ina microwave vessel, (6-phenylimidazo[1,2-b]pyridazin-3-yl)methanol(0.075 g, 0.33 mmol), 4-chloro-7-methoxyquinoline (0.19 g, 1.00 mmol),Cs₂CO₃ (0.22 g, 0.67 mmol) and 0.7 mL DMSO were combined and the vesselsealed. The mixture was pre-stirred for 2 min, followed by microwaveheating for 2 h at 120 C, then 1 h at 130 C. The mixture was allowed tocool to rt, diluted with water to precipitate a cream solid. The solidwas collected and rinsed with water. The solid was purified via flashchromatography using a 0% to 5% MeOH in EtOAc gradient to afford thetitle compound as a yellow solid. M/Z=383.2[M+H], calc 382.4212 forC₂₃H₁₈N₄O₂.

The following compounds were prepared using the method described for7-methoxy-4-((6-phenylimidazo[1,2-b]pyridazin-3-yl)methoxy)quinoline:

EXAMPLE 57

4-((6-(3-Fluorophenyl)imidazo[1,2-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline.M/Z=401.2 [M+H], calc 400.4113 for C₂₃H₁₇FN₄O₂.

EXAMPLE 58

4-((6-(3,4-Difluorophenyl)imidazo[1,2-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline.M/Z=419.2 [M+H], calc 418.4014 for C₂₃H₁₆F₂N₄O₂.

EXAMPLE 59

7-Methoxy-4-((6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)quinoline.In a 50 mL sealable flask was charged with PdCl₂(dppf)-CH₂Cl₂ adduct(0.011 g, 0.013 mmol),4-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline(0.150 g, 0.44 mmol), tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(0.18 g, 0.48 mmol), sat NaHCO₃ (0.75 ml, >0.97 mmol) and 4 mL dioxane.The vessel was sealed and the mixture heated at 80 C for 22 h. Themixture was allowed to cool to rt and diluted with EtOAc, the organiclayer washed with water, sat. NaHCO3, dried over Na₂SO₄, filtered andevaporated. The residue was dissolved in 5 mL CH₂Cl₂ and TFA (1.20 ml,16 mmol) was added. The mixture was stirred at rt for 10 min andevaporated. The residue was taken up into CH₂Cl₂ and stirred withminimal 2N NaOH for 1 h (ph basic). The mixture was evaporated andpurified by prep hplc. The title compound was obtained as an off-whitesolid. M/Z=457.3 [M+H], calc 456.5076 for C₂₄H₂₄N₈O₂.

EXAMPLE 603-Fluoro-7-methoxy-4-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)quinoline

A sealable tube was charged with Pd₂ dba₃ (0.20 g, 0.22 mmol),racemic-2-(di-t-butylphosphino)-1,1′-binaphthyl (0.18 g, 0.44 mmol),(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanol (0.100 g, 0.44mmol), 4-chloro-3-fluoro-7-methoxyquinoline (0.14 g, 0.66 mmol), cesiumcarbonate (0.29 g, 0.88 mmol), and toluene and sealed. The mixture washeated at 100 C for 12 h. The mixture was allowed to cool to rt and thesolid filtered, and rinsed with toluene. The solid was stirred with amixture of EA, MeOH, CH₂Cl₂ and filtered. The filtrate was purified viaflash chromatography using a MeOH in CH₂Cl₂ gradient. The resultingsolid was triturated with CH₂Cl₂/Hexanes then purified by prep hplc. Thetitle compound was collected as a white solid. M/Z=402.1 [M+H], calc401.3994 for C₂₂H₁₆FN₅O₂.

EXAMPLE 61

N-2-Phenyl-N-4-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)pyrimidine-2,4-diaminehydrochloride.2-Chloro-N-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)pyrimidin-4-amine(0.036 g, 0.11 mmol) was combined with 500 mL aniline and heated at 70 Cfor 2 h, at which point 300 mL aniline more was added and stirred anadditional 30 minutes. The mixture was allowed to cool to rt. Ether (5mL) was added and the mixture stirred. The title compound was collectedas a white solid. M/Z 395.2 [M+H], calc 394.4402 for C₂₂H₁₈N₈.

EXAMPLE 627-Methoxy-N-((6-(3,4,5-trifluorophenyl)imidazo[1,2-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine

a) (6-(3,4,5-Trifluorophenyl)imidazo[1,2-b]pyridazin-3-yl)methanamine.To a suspension of(6-(3,4,5-trifluorophenyl)imidazo[1,2-b]pyridazin-3-yl)methanol (0.442g, 1.6 mmol) in CH₂Cl₂ (5 mL) was added Mesyl-Cl (0.37 ml, 4.7 mmol) andtriethylamine (0.66 ml, 4.7 mmol)-slight exotherm, place flask in waterbath- and the mixture stirred at rt 1 h. The mixture was concentrated invacuo (without heating the flask) and the residue dissolved in DMF (2mL) and azidosodium (0.23 g, 3.5 mmol) was added in one portion. After45 minutes, additional azidosodium (0.40 g, 6.0 mmol) was added and themixture stirred 1 h longer. The mixture was diluted with EtOAc, washedwith water, brine, (back extract aq layer) and dry organic layer overNa₂SO₄, filter and evaporate. The azide intermediate was dissolved inTHF (4 mL) and trimethylphosphine 1M in THF (2.4 ml, 2.4 mmol) wasadded. The reaction mixture was stir at rt until the bubbling stops,plus an additional 2 minutes, then water (1 mL) was added. The mixturewas diluted with EtOAc, washed with NaHCO₃ solution, sat. NaHCO₃, (backextract aq layer), then dry organic layer over Na₂SO₄, filter andevaporate. The residue was purified via flash chromatography using al %NH₄OH in MeOH in CH₂Cl₂ gradient to afford the title compound as a tansolid.

b)7-Methoxy-N-((6-(3,4,5-trifluorophenyl)imidazo[1,2-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine.The title compound was prepared according to Method D, with the additionof 1 equivalent TFA. M/Z=437.1 [M+H], calc 436.3955 for C₂₂H₁₅F₃N₆O.

2-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one.In a sealable tube was combined Pd₂ dba₃ (0.0270 g, 0.0295 mmol),2-(dicyclohexylphosphino)-2′,4′,6′-tri-1-propyl-1,1′-biphenyl (0.0563 g,0.118 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(0.450 g, 1.77 mmol), 5-bromo-2-methylisoindolin-1-one (see Tsuritani,T., et al Synlett 2006, 5 801-803) (0.267 g, 1.18 mmol), potassiumacetate (0.232 g, 2.36 mmol) and 2 mL dioxane. The mixture was blanketedwith N₂, sealed and heated at 80 C for 22 h. The mixture was allowed tocool to rt then diluted with EtOAc, and the organic layer washed withwater, sat. NaHCO₃, then dried over Na₂SO₄, filtered and evaporated. Theresidue was purified via flash chromatography using a EtOAc in CH₂Cl₂gradient. The title compound was collected as a tan solid.

tert-Butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate.The title compound was prepared according procedures known in the art.

1-Ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. A150 mL sealable tube was charged with Pd₂ dba₃ (0.216 g, 0.235 mmol),2-(dicyclohexylphosphino)-2′, 4′,6′-tri-1-propyl-1,1′-biphenyl (0.224 g,0.471 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(7.47 g, 29.4 mmol), 4-bromo-1-ethyl-1H-pyrazole (see Ivachtchenko, A.V., et al J. Het. Chem. 2004, 41, 931-939) (4.12 g, 23.5 mmol),potassium acetate (4.62 g, 47.1 mmol) and dioxane (10 mL). The mixturewas blanketed with N₂, the vessel sealed and heated at 85 C for 22 h.Allow the mixture to cool to rt and dilute with EtOAc, wash with water,sat. NaHCO₃, then dry organic layer over Na₂SO₄, filter and evaporate.The mixture was purified via flash chromatography using an EtOAc inCH₂Cl₂ gradient. Use 12 stain to develop tlc (compound not uv active at254). The title compound was collected as a mixture with pinacoldiborane.

1-(2-Methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.The title compound was prepared in the same manner as1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole,using 1-(2-methoxyethyl)-4-bromo-1H-pyrazole (see Ivachtchenko, A. V.,et al J. Het. Chem. 2004, 41, 931-939).

6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo dithiazole.Prepared from 6-bromobenzo[d]thiazole according to the above procedures.

1-Cyclobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

a) 4-Bromo-1-cyclobutyl-1H-pyrazole. To a cooled (0 C) stirred solutionof 4-bromo-1H-pyrazole (5.360 g, 36.47 mmol) in DMF (50 mL) was addedsodium hydride (1.925 g, 80.23 mmol) slowly. The mixture was allowed tostir in the ice bath 30 min and bromocyclobutane (3.433 ml, 36.47 mmol)was added. The vessel was sealed and the reaction mixture heated at 95 Cfor 23 h. The mixture was allowed to cool to rt and diluted with 200 mLEtOAc, washed with 500 mL water, then 2×100 mL water, sat NaHCO₃, thenthe organic layer dried over Na₂SO₄, filtered and evaporated. Themixture was purified via flash chromatography using a CH₂Cl₂ in hexanesgradient. (12 stain for visualization). The title compound was collectedas a colorless liquid.

b)1-Cyclobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.The title compound was prepared in the same manner as described for1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

1-Isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

a) 4-bromo-1-isopropyl-1H-pyrazole. A sealable vessel was charged withpotassium carbonate (3.76 g, 27.2 mmol), 4-bromo-1H-pyrazole (4.00 g,27.2 mmol), and 10 mL DMF. To this mixture, 2-iodopropane (3.27 ml, 32.7mmol) was added and the vessel sealed. The mixture was heated at 80 Cfor 16 h and allowed to cool to rt. The mixture was diluted with EtOAc,extracted with water, water, sat NaHCO3, and the organic layer driedover Na₂SO₄, filtered and evaporated. The mixture was purified via flashchromatography using a EtOAc in CH2Cl2 gradient. The desired compound(as determined by TLC, 12 stain) was collected as a colorless liquid.

b)1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.The title compound was prepared in the same manner as described for 1ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

EXAMPLE 63

Intermediate4-((6-(6-fluoropyridin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinolinewas prepared as described in general Method A.

5-(3-((7-Methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyridin-2(1H)-one

4-((6-(6-Fluoropyridin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline(0.121 g, 0.30 mmol) was suspended in dioxane (1 mL) then added 3Maqueous hydrochloric acid (2.0 ml, 6.0 mmol). The reaction mixture wasthen heated at 100° C. for 1 hour. The mixture was concentrated undervacuum and the remaining solid was dissolved in methanol (4 mL) thenadded triethylamine (0.42 ml, 3.0 mmol). The mixture was stirred at roomtemperature for 1 hour then concentrated under vacuum. The sample waspurified by flash chromatography eluting with 15% 7N NH₃ inmethanol/dichloromethane to afford5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyridin-2(1H)-oneas a pale orange solid.

EXAMPLE 64

4-(3-((7-Methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyridin-2(1H)-onewas prepared as previously described for5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyridin-2(1H)-one.

EXAMPLE 65 Synthesis of the Hydrazine Intermediate

Step 1. 3,6-Dichloro-4-methylpyridazine (1.00 g, 6.1 mmol) was mostlydissolved in dioxane (22.5 mL) then added phenylboronic acid (0.82 g,6.7 mmol), PdCl₂(dppf)-CH₂Cl₂Adduct (0.25 g, 0.31 mmol) and a solutionof cesium carbonate (6.0 g, 18 mmol) in water (7.5 mL). The reactionmixture was heated at 80° C. for 6 hours. The reaction mixture wasconcentrated under vacuum and the remaining solid was triturated withwater. The solid was collected on a glass frit, washing well with water.The sample was purified by flash chromatography eluting with 1:4 ethylacetate/hexane to afford 3-chloro-4-methyl-6-phenylpyridazine as anoff-white solid.

MS (ESI pos. ion) m/z: 205.2 (MH⁺).

Step 2. 3-Chloro-4-methyl-6-phenylpyridazine (0.510 g, 2.49 mmol) wasdissolved in hydrazine (1.56 ml, 49.8 mmol) then the reaction mixturewas heated at 100° C. for 1.5 hours. The precipitate that had formed inthe mixture was collected and washed with ^(i)PrOH. The solid was driedunder high vacuum to afford 1-(4-methyl-6-phenylpyridazin-3-yl)hydrazineas a pale yellow solid.

MS (ESI pos. ion) m/z: 201.1 (MH⁺).

The remaining synthesis of7-methoxy-N-((8-methyl-6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-aminewas conducted as described in general Method B.

Synthesis of the1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-oneIntermediate

Step 1. 5-Bromopyridin-2(1H)-one (0.250 g, 1.44 mmol) was dissolved inDMF (3 mL) then added iodomethane (0.0943 ml, 1.51 mmol) and potassiumcarbonate (0.218 g, 1.58 mmol). The reaction was stirred at roomtemperature overnight. The reaction mixture was concentrated undervacuum. The remaining residue was dissolved in ethyl acetate then washedwith water and brine. The aqueous layer was back-extracted with ethylacetate (3×). The organic layers were combined and dried over sodiumsulfate then concentrated under vacuum to afford5-bromo-1-methylpyridin-2(1H)-one as an orange waxy solid.

MS (ESI pos. ion) m/z: 188.0 and 190.0 (MH⁺).

Step 2. 5-Bromo-1-methylpyridin-2(1H)-one (0.100 g, 0.532 mmol) wassuspended in dioxane (2 mL) then added4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(0.203 g, 0.798 mmol), PdCl2(dppf)-CH2Cl2Adduct (0.0217 g, 0.0266 mmol)and sodium acetate (0.109 g, 1.33 mmol). The reaction mixture was heatedat 120° C. for 5.5 hours then at 130° C. for 3 hours. The reactionmixture was filtered through a pad of Celite, washing with MeOH. Thefiltrate was concentrated under vacuum. The remaining black residue wasthen dissolved in dichloromethane and filtered through another pad ofCelite, washing well with dichloromethane. The filtrate was concentratedunder vacuum and the remaining black residue was further dried underhigh vacuum to afford1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-oneas a black solid.

MS (ESI pos. ion) m/z: 236.1 (MH⁺).

EXAMPLE 66

Intermediate 3-(4-methoxybenzyl)-6-phenyl-[1,2,4]triazolo[4,3-a]pyridinewas prepared as described in general Method A.

4-((6-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)phenol

3-(4-Methoxybenzyl)-6-phenyl-[1,2,4]triazolo[4,3-a]pyridine (0.057 g,0.18 mmol) was dissolved in dichloromethane (2.5 mL) then cooled to 0°C. A 1M solution of boron tribromide (0.72 ml, 0.72 mmol) indichloromethane was added slowly. The reaction mixture was stirred at 0°C. for 2 hours. A precipitate was present in the reaction mixture. Thereaction was quenched with ice chips and stirred overnight at roomtemperature. A solid remained in the mixture. The reaction mixture wasdiluted with dichloromethane/methanol to give a clear mixture thenwashed with saturated aqueous sodium bicarbonate and brine. The organiclayer was dried over sodium sulfate and concentrated under vacuum. Thesample was purified by preparative TLC eluting with 7% methanol indichloromethane which afforded4-((6-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)phenol as anoff-white solid

EXAMPLE 67

4-((6-(Pyridin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)phenolwas prepared as previously described for4-((6-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)phenol.

EXAMPLE 68

4-((6-(Pyrazin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)phenolwas prepared as previously described for4-((6-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)phenol.

EXAMPLE 69

4-((6-(1H-Pyrrol-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)phenolwas prepared as previously described for4-((6-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)phenol.

6-bromoquinoxaline

To a solution of 4-bromobenzene-1,2-diamine (4.0 g, 21 mmol) in 60 mL ofEtOH was added 40% glyoxal aldehyde (4.1 ml, 32 mmol) solution in water.The resulting mixture was refluxed for 10 hours. The mixture wasconcentrated in vacuo and the residue was diluted in, 100 mL of EtOAc.The organic solution was washed with 40 mL of satd. NaHCO₃ and 40 mL ofbrine, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by a silca gel column chromatography (5% EtOAc/hex to EtOAC) togive light yellow solid 6-bromoquinoxaline. MS (ESI, pos. ion) m/z:208.9 (M+1).

tert-butyl 2-(quinoxalin-6-yl)acetate

To a solution of 6-bromoquinoxaline (1.40 g, 7 mmol),tris(dibenzylideneacetone)dipalladium (0) (0.6 g, 0.7 mmol) and Q-phos(1.0 g) in 25 mL of THF was added Reactant 2 (27 ml, 27 mmol) three timein 3 hours. The reaction was heated at 50° C. for 16 hours and wasquenched with 50 mL of satd. NH4Cl. The mixture was diluted with 60 mLof EtOAc. The organic phase was separated, washed with brine, dried overNa2SO4 and concentrated in vacuo to give red oil. The residue waspurified by a silica gel column chromatography (5% EtOAc/hex to EtOAC)twice to give red solid tert-butyl 2-(quinoxalin-6-yl)acetate. MS (ESI,pos. ion) m/z: 245.1 (M+1).

6-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoxaline

A mixture of tert-butyl 2-(quinoxalin-6-yl)acetate (0.15 g, 0.6 mmol),1-(6-phenylpyridazin-3-yl)hydrazine (0.1 g, 0.7 mmol) andp-toluenesulfonic acid monohydrate (0.1 g, 0.6 mmol) in 3 mL of dioxanewas heated with microwave at 150° C. for 1 hour in a microwave tube. Themixture was diluted with 70 mL of EtOAc and 40 mL of satd. NaHCO₃solution. The organic phase was separated and was washed with 40 mL ofbrine, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by a silica gel column chromatography (EtOAc to 15% MeOH/EtOAc)to give light yellow solid as desired product6-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoxaline.

6-bromoquinazolin-4(3H)-one

A solution of 5-bromoisatoic anhydride (5.0 g, 21 mmol) andformamidinium acetate (2.2 g, 21 mmol) in 60 mL of i-PrOH was heated atreflux for 10 hours. The reaction mixture was cooled to rt and the whitesolid was collected by filtration. The white solid was washed with smallamount of i-PrOH and dried in air to give desired product6-bromoquinazolin-4(3H)-one. MS (ESI, pos. ion) m/z: 224.9 (M+1).

tert-butyl 2-(4-oxo-3,4-dihydroquinazolin-6-yl)acetate

To a solution of 6-bromoquinazolin-4(3H)-one (1.00 g, 4 mmol),tris(dibenzylideneacetone)dipalladium (0) (0.4 g, 0.4 mmol) and Q-phos(0.8 g) in 25 mL of THF was added Reactant 2 (27 ml, 13 mmol) three timein 5 hours. The reaction was heated at 50° C. for 16 hours and wasquenched with 50 mL of satd. NH₄Cl. The mixture was diluted with 60 mLof EtOAc. The organic phase was separated, washed with brine, dried overNa2SO4 and concentrated in vacuo to give red oil. The residue waspurified by a silica gel column chromatography (5% EtOAc/hex to EtOAC)twice to give orange solid tert-butyl2-(4-oxo-3,4-dihydroquinazolin-6-yl)acetate. MS (ESI, pos. ion) m/z:261.1 (M+1).

2-(4-oxo-3,4-dihydroquinazolin-6-yl)acetic acid

A solution of tert-butyl 2-(4-oxo-3,4-dihydroquinazolin-6-yl)acetate(0.25 g, 0.96 mmol) in 10 mL of satd.HCl in EtOAc was stirred at rt for4 hours. The mixture was concentrated in vacuo at rt, and the residuewas used in the next reaction without further purification. MS (ESI,pos. ion) m/z: 205.1 (M+1).

EXAMPLE 706-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinazolin-4(3H)-one

A mixture of 2-(4-oxo-3,4-dihydroquinazolin-6-yl)acetic acid (0.10 g,0.5 mmol), 1-(6-phenylpyridazin-3-yl)hydrazine (0.1 g, 0.6 mmol) andp-toluenesulfonic acid monohydrate (0.09 g, 0.5 mmol) in 3 mL of dioxanewas heated with microwave at 150° C. for 1 hour in a microwave tube. Themixture was diluted with 70 mL of EtOAc and 40 mL of satd. NaHCO3solution. The organic phase was separated and was washed with 40 mL ofbrine, dried over Na2SO4 and concentrated in vacuo. The residue waspurified by a silica gel column chromatography (EtOAc to 15% MeOH/EtOAc)to give light yellow solid as desired product6-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinazolin-4(3H)-one.MS (ESI, pos. ion) m/z: 355.1 (M+1).

EXAMPLE 716-(1-(6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline

To a solution of 5-bromo-3-methylisothiazole (1.00 g, 5.6 mmol) in 10 mLof THF at −45° C. (CH₃CN/dry ice) was added isopropylmagnesium chlorideLiCl complex (7.9 ml, 7.9 mmol) (LiCl complex, 1M in THF). The mixturewas stirred at −45° C. for 20 minutes and was added zinc chloride, 0.5 min thf (17 ml, 8.4 mmol) slowly via a syringe. The mixture was thenwarmed up to rt and continued to stir for additional 30 minutes.6-(1-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline(0.5787 g, 1.9 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.51 g,0.56 mmol) and Q-Phos (0.65 g) in 15 mL of N,N-dimethyl acetamide wasadded to the reaction mixture. The reaction was warmed up to 50° C. for6 h and was quenched with 50 mL of satd. NH₄Cl aq. solution. The mixturewas extracted with 150 mL of EtOAc and the organic phase was washed with60 mL of brine. The aqueous phases were extracted with 100 mL EtOAcagain. The combined organic phases were dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by a silica gel columnchromatography (EtOAc to 15% MeOH in EtOAc) to give red solid as desiredproduct6-(1-(6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline.MS (ESI, pos. ion) m/z: 373.2 (M+1).

Methyl2-fluoro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzoate(0.368 g, 0.803 mmol) was diluted with dioxane (17 mL) and to thesolution was added lithium hydroxide (0.0384 g, 1.61 mmol) in water (8mL). The reaction mixture was heated at 40° C. for 4.5 hours. Thereaction mixture was concentrated in vacuo to remove most of the dioxaneand water (not concentrated to dryness).

To the crude mixture, water (8 mL) was added. Dropwise, 1N HCl was addedto pH=7. The neutral solution was then filtered through a frit and thecrude solid product was washed with MeCN and a small amount of MeOH. Thefinal acid product was concentrated, and carried on to the acidchloride.

To a suspension of2-fluoro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzoicacid (0.150 g, 0.338 mmol) in DCM (1.5 mL) at 0° C. was added dropwisethionyl chloride (0.370 ml, 5.06 mmol). DMF (1 drop) was added and thesolution was allowed to stir at room temperature for 5 h. The reactionmixture was concentrated in vacuo to a light brown solid. The materialwas taken on crude for synthesis of the following amide.

EXAMPLE 722-fluoro-N-(2-methoxyethyl)-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide

To a solution of N-ethyl-N-isopropylpropan-2-amine (0.077 ml, 0.44 mmol)and2-fluoro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzoylchloride-HCl (0.088 g, 0.18 mmol) in DCM (1.25 mL) was added2-methoxyethanamine (0.023 ml, 0.26 mmol) dropwise. The solution wasstirred at room temperature for 5 h. The crude material was concentratedand then triturated with sodium bicarbonate and washed with water. Theresultant solid was dissolved in DCM/MeOH and concentrated.

The crude material was dissolved in DCM/MeOH and was purified via flashchromatography, eluting with 0-10% MeOH/NH₄OH in DCM to yield2-fluoro-N-(2-methoxyethyl)-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide.

EXAMPLE 73

tert-butyl4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)phenyl(methyl)carbamate(0.067 g, 0.13 mmol) was dissolved in MeOH (1.7 mL) and to the solutionwas added concentrated HCl (0.50 ml, 6.0 mmol). The reaction mixture wasstirred at room temperature overnight. Upon completion, the crudemixture was concentrated in vacuo.

The solid that remained after concentration was dissolved in MeOH and tothe solution was added triethylamine (0.23 ml, 1.6 mmol). The reactionwas allowed to stir for 1 h. The crude mixture was concentrated invacuo.

The compound was purified using via flash chromatography, eluting with5-8% MeOH/NH₄OH in DCM to yield4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-N-methylbenzenamineas a yellow solid.

EXAMPLE 74

A solution of2-fluoro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzoicacid (0.192 g, 0.43 mmol), HATU (0.26 g, 0.69 mmol), and Hunig's Base(0.30 ml, 1.7 mmol) in DMF (10.75 mL) was allowed to stir for 30minutes. Ammonia (0.0093 ml, 0.43 mmol) was then bubbled through themixture for another 30 minutes.

The solution was concentrated in vacuo and purified using via flashchromatography, eluting with 5-10% MeOH/NH₄OH in DCM. There remained anunidentified peak in the NMR, so the solid was triturated in MeCN,filtered, and quickly washed with DCM to wash through the impurities.Concentration in vacuo yielded2-fluoro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamideas an off-white solid.

EXAMPLE 75

To a solution of5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)thiophene-2-carbonylchloride (0.150 g, 0.33 mmol) and Hunig's Base (0.17 ml, 1.00 mmol) inDCM (2.5 mL) was added methanamine (0.17 ml, 0.33 mmol) in THF dropwise.The solution was stirred at room temperature for 3 hours, at which pointan additional 1.5 equivalents of amine were added.

The solution was concentrated in vacuo and purified via flashchromatography eluting with 3-8% MeOH:NH₄OH in DCM. There remained animpurity, so the product was triturated with MeCN, filtered and washedwith DCM to yield5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-N-methylthiophene-2-carboxamide(0.0276 g, 19% yield) as an amorphous tan solid.

EXAMPLE 76

6-((6-Phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline. To a50 ml round-bottomed flask was added 2-(quinolin-6-yl)acetic acid (0.60g, 3.2 mmol), CH₂Cl₂ (20 ml) and oxalyl chloride (4.0 ml, 8.0 mmol, 2 Min CH₂Cl₂) and DMF (0.2 mL of a solution of 1 drop DMF in 1 mL CH₂Cl₂).After 3 d, an additional 2.5 eq. of oxalyl chloride was added. After 4h, toluene (1 mL) was added and the mixture was concentrated. Toluene (3mL) was added and again concentrated. The residue was taken up in CH₂Cl₂(20 mL) and 1-(6-phenylpyridazin-3-yl)hydrazine (0.60 g, 3.2 mmol) wasadded. The mixture was stirred for 17 h and then concentrated. Themixture was then taken up in phosphorous oxychloride (20 ml, 220 mmol)and heated at 100° C. for 15 h. Toluene (5 mL) was added and thesolution was concentrated. Another 5 mL toluene was added to the residueand once again it was concentrated. The brown solid residue was taken upin sat. NaHCO₃ and extracted with EtOAc (4×150 mL) and 25% iPrOH/CHCl₃(3×150 mL). The combined extracts were washed with brine, dried (Na₂SO₄)and concentrated onto silica. Purification by silica gel chromatography(0 to 5% MeOH (2M in NH₃)/CH₂Cl₂) afforded the title compound as a tansolid. MS (ESI, pos. ion) m/z: 338 (M+1).

Methyl 2-(quinolin-6-yl)propanoate. To a 250 ml round-bottomed flask wasadded lithium bis(trimethylsilyl)amide (2.0 g, 12 mmol) andtetrahydrofuran (75 ml). The mixture was cooled to −78° C. and methyl2-(quinolin-6-yl)acetate (2.0 g, 9.9 mmol) was added as a solution in 1ml THF. This was stirred at −78° C. for 30 min and then methyl iodide(0.75 ml, 12 mmol) was added. This was stirred for 30 min at −78° C. andthen allowed to warm to rt. The mixture was quenched with sat NH₄Cl (40mL) and diluted with water (200 mL). The mixture was concentrated invacuo to remove the THF and then was extracted with EtOAc (2×100 ml).The combined extracts were washed with brine (50 ml), dried (Na₂SO₄) andconcentrated onto silica. Purification by silica gel chromatography (20to 60% EtOAc/hexane) afforded the title compound as a brown oil (1.8 g,85%). MS (ESI, pos. ion) m/z: 216 (M+1).

2-(Quinolin-6-yl)propanoic acid. To a 15 ml round-bottomed flask wasadded methyl 2-(quinolin-6-yl)propanoate (1.0 g, 4.7 mmol), methanol(5.0 ml, 12 mmol) and aq. sodium hydroxide (5 M, 2.3 ml, 12 mmol). Themixture was stirred at 25° C. for 24 h. The mixture was neutralized withaq. HCl (5 M, 2.3 mL, 12 mmol). After sitting overnight a whiteprecipitate had formed. The mixture was filtered and the filtercake waswashed with water and then dried in vacuo to afford the title compoundas a white solid (0.72 g, 77%). MS (ESI, pos. ion) m/z: 202 (M+1).

EXAMPLE 77

6-(1-(6-Phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline. Toa 2-5 ml Personal Chemistry microwave vial was added2-(quinolin-6-yl)propanoic acid (0.25 g, 1.2 mmol),1-(6-phenylpyridazin-3-yl)hydrazine (0.42 g, 2.2 mmol) and conc. HCl (2mL). The mixture was heated in the microwave at 160° C. for 8 h. Aftercooling to rt, the mixture was poured into sat. NaHCO₃ (100 mL) and thenextracted with EtOAc (4×75 mL). The combined extracts were washed withbrine, dried (Na₂SO₄) and concentrated onto silica. Purification bysilica gel chromatography (1.0 to 4.5% MeOH (2 M in NH₃)/CH₂Cl₂)afforded the title compound as an off-white solid (0.23 g, 53% yield).MS (ESI, pos. ion) m/z: 352 (M+1).

EXAMPLE 78(S)-6-(1-(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline

Isolated from chiral separation of6-(1-(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline.Column: Chiralpak AS-H (250×21 mm). Mobile Phase: A: Liquid CO₂. B:Methanol (0.1% DEA). Isocratic: 75:25 (A:B). Flow rate: 70.0 mL/min.Outlet Pressure: 100 bar. Retention time: 4.38 min. Enantiomericpurity: >99% ee. MS (ESI, pos. ion) m/z: 352 (M+1).

EXAMPLE 79

(R)-6-(1-(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline(AMG 2121451). Isolated from chiral separation of6-(1-(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline.Column: Chiralpak AS-H (250×21 mm). Mobile Phase: A: Liquid CO₂. B:Methanol (0.1% DEA). Isocratic: 75:25 (A:B). Flow rate: 70.0 mL/min.Outlet Pressure: 100 bar. Retention time: 4.90 min. Enantiomeric purity:96.8% ee. MS (ESI, pos. ion) m/z: 352 (M+1).

Methyl 2-fluoro-2-(quinolin-6-yl)acetate. To a 250 ml round-bottomedflask was added lithium bis(trimethylsilyl)amide (2.0 g, 12 mmol) andtetrahydrofuran (75 ml). The mixture was cooled to −78° C. and methyl2-(quinolin-6-yl)acetate (2.0 g, 9.9 mmol) was added as a solution in 1ml THF. After stirring at −78° C. for 30 min, n-fluorobenzenesulfonimide(3.8 g, 12 mmol) was added as a 1 M solution in THF. This was stirredfor 30 min at −78° C. and then allowed to warm to rt. The mixture wasquenched with sat NH₄Cl (50 mL) and diluted with water (200 mL). Themixture was concentrated in vacuo to remove the THF and then wasextracted with EtOAc (2×100 ml). The combined extracts were washed withbrine (100 ml), dried (Na₂SO₄) and concentrated onto silica.Purification by silica gel chromatography (20 to 60% EtOAc/hexane)afforded the title compound as a tan solid. MS (ESI, pos. ion) m/z: 220(M+1).

2-Fluoro-2-(quinolin-6-yl)acetic acid. To a solution containing methyl2-fluoro-2-(quinolin-6-yl)acetate (0.49 g, 2.2 mmol) in methanol (3.0ml) was added sodium hydroxide (5 M, 1.0 ml, 5.0 mmol). The mixture wasstirred at rt for 48 h and then neutralized with 5 N HCl (1.0 mL). Thesolution was allowed to sit overnight during which time a precipitateformed. The solution was filtered and the filtercake washed with coldwater then dried under vacuum to afford the title compound as a tansolid. MS (ESI, pos. ion) m/z: 206 (M+1).

EXAMPLE 80

(6-Phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)(quinolin-6-yl)methanolTFA salt. To a 2-5 ml Personal Chemistry microwave vial was added2-fluoro-2-(quinolin-6-yl)acetic acid (0.20 g, 0.98 mmol),1-(6-phenylpyridazin-3-yl)hydrazine (0.27 g, 1.5 mmol) and conc.hydrochloric acid (2.0 ml, 66 mmol). The mixture was heated at 160° C.for 6 h in the microwave. After cooling to rt, the mixture was pouredinto sat. NaHCO₃ (100 mL) and extracted with 25% iPrOH/CHCl₃ (4×50 mL).The combined extracts were dried (Na₂SO₄) and concentrated onto silica.Purification by silica gel chromatography (2.0 to 6.5% MeOH (2 M inNH₃)/CH₂Cl₂) followed by further purification by Prep-HPLC (PhenomenexSynergi 4u MAX-RP 80A 150×21.20 mm, 10 to 65% CH₃CN(0.1% TFA)/H₂O(0.1%TFA) over 15 min then 65% CH₃CN for 5 minutes at 20 ml/min) with thefractions containing product concentrated to afford the title compoundas a tan solid (0.10 g, 22% yield). MS (ESI, pos. ion) m/z: 354 (M+1).

EXAMPLE 81(R)-(6-Phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)(quinolin-6-yl)methanol

Isolated from chiral separation of racemic(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)(quinolin-6-yl)methanolTFA salt (AMG 2120533). Column: Chirotechnology AS-H column, 4.6 mm×15cm. Mobile phase: 70/30 Carbon dioxide/0.2% diethylamine in ethanol.Flow rate: 4.0 mL/min. Temperature: 40° C. Back pressure: 100 bar.Retention time: 1.65 min. Enantiomeric purity: >99% ee. MS (ESI, pos.ion) m/z: 354 (M+1).

EXAMPLE 82(S)-(6-Phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)(quinolin-6-yl)methanol

Isolated from chiral separation of racemic(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)(quinolin-6-yl)methanolTFA salt (AMG 2120533). Column: Chirotechnology AS-H column, 4.6 mm×15cm. Mobile phase: 70/30 Carbon dioxide/0.2% diethylamine in ethanol.Flow rate: 4.0 mL/min. Temperature: 40° C. Back pressure: 100 bar.Retention time: 2.22 min. Enantiomeric purity: >99% ee. MS (ESI, pos.ion) m/z: 354 (M+1).

Step 1: 4-amino-3-bromo-2-chloropyridine. 4-amino-2-chloropyridine (50g, 388 mmol) was dissolved in glacial acetic acid (500 mL). To thissolution was added N-bromosuccinamide (75 g, 426 mmol,) portionwise atroom temperature (water bath cooling was provided to control theexothermicity). The reaction mixture was stirred at RT for 1 h at whichpoint the reaction was found complete (as monitored by TLC). Solvent wasremoved under reduced pressure followed by azeotropic distillation withethanol. The crude product was purified by column chromatography onsilica gel (230-400 mesh) eluting with ethyl acetate hexane mixture.

Step 2: 4-amino-3-bromo-2-methoxypyridine. Methanol (350 mL) was chargedin a two-neck round bottom flask e quipped with a guard tube and septumand cooled to 0° C. Sodium metal (23 g) was added to it slowly inpieces. After all sodium metal had dissolved, 4-amino-3-bromo-2-chloropyridine (23 g, 178 mmol) was added and the solution was heated at 180°C. in a pressure vessel for 5-6 h. The reaction mixture was then cooledto 0° C. and adjusted to pH 8 by addition of conc. HCl. Solvent wasremoved under reduced pressure and the residue was suspended in ethylacetate. Undissolved impurities were removed by filtration and thefiltrate was concentrated under reduced pressure to obtain pure product.

Step 3:5-[(3-Bromo-2-methoxy-pyridin-4-ylamino)-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione.A two necked round bottomed flask equipped with a reflux condenser wascharged with Meldrum's acid (15.6 g, 108 mmol) and trimethylorthoformate (143 mL). The reaction mixture was heated 100° C. for 2 h.4-amino-3-bromo-2-methoxypyridine (22 g, 108 mmol) was added and heatingwas continued for an additional 4 h at 100° C. The reaction mixture wasallowed to cool to RT, diluted with hexane and filtered to obtain theproduct as a yellow solid.

Step 4: 8-Bromo-7-methoxy-1H-[1,6]naphthyridin-4-one. A two neck roundbottomed flask equipped with an air condenser was charged with5-[(3-Bromo-2-methoxy-pyridin-4-ylamino)-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione(23 g, 64 mmol) and diphenyl ether (230 mL). The reaction mixture washeated at 250° C. for 30 min under nitrogen atmosphere after which itwas cooled to RT, diluted with hexane and filtered to obtain a darksolid. The crude product was refluxed in hexane for 30 min and filteredto obtained 8-Bromo-7-methoxy-1H-[1,6]naphthyridin-4-one as a brownsolid.

Step 5: 7-Methoxy-1H-[1,6]naphthyridin-4-one.8-Bromo-7-methoxy-1H-[1,6]naphthyridin-4-one (12 g, 33.5 mmol) wasdissolved in anhydrous methanol (240 mL) and 10% Dry Pd/C (2.4 g) wasadded carefully in portions. This was followed by portionwise additionof ammonium formate (24 g) which caused an exotherm. The reactionmixture was heated to reflux for 1 h. The reaction mixture was cooled toroom temperature, filtered through Celite, and washed with hot methanol.The filtrate was concentrated and the residue purified by columnchromatography on silica gel (230-400 mesh) eluting with ethylacetate-methanol.

Step 6: 4-Chloro-7-methoxy-[1,6]naphthyridine. A two neck round bottomedflask equipped with CaCl₂ guard tube was charged with7-Methoxy-1H-[1,6]naphthyridin-4-one (28 g, 159 mmol) and POCl₃ (280mL). The reaction mixture was stirred at RT for 3 h. The reactionmixture was poured into ice water and the pH was carefully adjusted to 8with solid sodium carbonate (highly exothermic reaction). The productwas extracted with EtOAc. The combined organic layer was washed withwater, dried over Na₂SO₄ and concentrated. The crude product waspurified by column chromatography on silica gel (230-400 mesh) elutingwith ethyl acetate hexane mixture.

Step 1: 3-Bromo-5-methoxypyridine. Sodium (12 g) was dissolved inmethanol (150 mL) while cooling, and excess MeOH was removed underreduced pressure to obtain NaOMe, which was azeotroped with toluene(2×100 mL). A solution of 3,5-dibromopyridine (100 g) in DMSO (500 mL)was added to sodium methoxide and the mixture was stirred at 90° C. for2 h. After cooling to RT, aqueous NaOH solution (3 M, 300 mL) was addedand the mixture was extracted with Et₂O. The ethereal layer was washedwith brine and dried over Na₂SO₄. After concentration the crude productobtained was purified by flash column chromatography (Hexane:EtOAc85:15) to afford pure product 3-bromo-5-methoxy pyridine.

Step 2: 3-amino-5-methoxypyridine. 3-Bromo-5-methoxypyridine (15 g) wasadded to a pressure vessel, and CuSO₄ (3.9 g) and 25% aq. ammonia (150mL) were added. The reaction mixture was stirred for 4 h at 135° C.,then cooled to RT, basified with aqueous NaOH solution, and extractedwith CH₂Cl₂. After evaporation of volatiles, 3-amino-5-methoxypyridinewas obtained as yellow solid.

Step 3:5-[(5-Methoxy-pyridin-3-ylamino)-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione.A two-necked round bottomed flask equipped with a reflux condenser wascharged with Meldrum's acid (14.4 g, 100 mmol) and trimethylorthoformate(100 mL). The reaction mixture was heated at 100-105° C. for 2 h.5-amino-3-methoxy pyridine (12.5 g, 100 mmol) was added to the reactionmixture and heating was continued for an additional 4 h at the sametemperature. The reaction mixture was allowed to cool to RT, dilutedwith hexane and filtered to obtain the product as light yellow solid.

Step 4: -Methoxy-1H-[115]naphthyridin-4-one. A two-necked round bottomedflask equipped with an air condenser was charged with5-[(5-Methoxy-pyridin-3-ylamino)-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione(18 g) and diphenyl ether (180 mL). The reaction mixture was heated at240-250° C. for 5 min under N₂ atmosphere after which it was cooled toRT, diluted with hexane and filtered to obtain a dark solid. The crudeproduct was refluxed in hexane for 30 min and filtered to obtain productas a brown solid.

Step 5: 8-chloro-3-methoxy-1,5-naphthyridine. A two-necked roundbottomed flask equipped with an air condenser (protected with CaCl₂guard tube) was charged with 7-Methoxy-1H-[1,5]naphthyridin-4-one (13 g)and POCl₃ (65 mL). The reaction mixture was allowed to reflux at 120° C.for 12 h. The POCl₃ was removed in vacuo and azeotroped twice withtoluene. EtOAc (75 mL) was added and the reaction mixture was stirred at50-60° C. for 15-20 min. EtOAc removed separated by decantation. Theorganic layers were combined and concentrated. The obtained crude wasdissolved in EtOAc (50 ml) and a washed with satd. aqueous sodiumbicarbonate. The organic layer was dried over Na₂SO₄ and concentrated.The resulting solids were suspended in hexane, stirred for 15 min,filtered and dried under vacuum.

EXAMPLE 837-(difluoromethoxy)-N-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine

DMF (0.5 mL) and water (0.1 mL) were added to a pressure vesselcontaining8-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylamino)-1,5-naphthyridin-3-ol(50 mg, 135 μmol), sodium 2-chloro-2,2-difluoroacetate (47 mg, 311μmol), cesium carbonate (62 mg, 190 μmol). The reaction mixture wasstirred at 100° C. for 18 h, cooled to RT and concentrated in vacuo.Purification by MPLC (DCM/MeOH+1% NH₄OH: 100/0 to 90/10) afforded thetitle compound (10 mg, 17% yield). MS m/z=420.1 [M+H]⁺. Calc'd for C,21; H, 15; F, 2; N, 7O, : 419.40.

EXAMPLE 84N-((6-(3H-1,2,3-triazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine 1)Preparation of tert-butyl(6-(3H-1,2,3-triazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate

tert-Butyl(6-ethynyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (0.109g, 0.399 mmol) and sodium azide (0.0285 g, 0.439 mmol) were dissolvedDMF (2 mL) at RT. The reaction mixture was stirred overnight at RT thenat 70° C. for 3 h. Water was added at RT and the aqueous layer wasextracted with EtOAc and 1-butanol. The organic extracts were washedwith brine, dried over MgSO₄, filtered and concentrated in vacuo. Usedwithout further purification.

2) Preparation ofN-((6-(3H-1,2,3-triazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine

Prepared by a method similar to7-methoxy-N-((6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine.MS m/z=375.1 [M+H]⁺. Calc'd for C, 17; H, 14; N, 10; O: 374.37

EXAMPLE 854-((8-fluoro-6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-methoxyquinoline

Dioxane (3.6 mL) was added to4-((6-chloro-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-methoxyquinoline(175 mg, 488 μmol), X-Phos (32.6 mg, 68.3 μmol),3-methyl-5-(trimethylstannyl)isothiazole (153 mg, 585 μmol), palladiumacetate (7.67 mg, 34.1 μmol). The flask was purged with argon andsealed. The reaction mixture was stirred at 80° C. for 2d. More X-Phos(32.6 mg, 68.3 μmol), palladium acetate (7.67 mg, 34.1 μmol) and3-methyl-5-(trimethylstannyl)isothiazole (153 mg, 585 μmol) were addedand stirring was continued at 80° C. overnight. The reaction mixture wascooled at RT, concentrated in vacuo and urified by MPLC (CH₂Cl₂/MeOH:100/0 to 90/10). Further purification by MPLC (ISCO, EtOAc/MeOH: 9/1,isocratic) afforded the title compound (105 mg, 51% yield). MS m/z=422.0[M+H]⁺. Calc'd for C₂₁H₁₆FN₅O₂S: 421.46

EXAMPLE 864-((8-fluoro-6-(2-methylthiazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-methoxyquinoline 1)Preparation of 2-methyl-5-(trimethylstannyl)thiazole

Butyllithium (1.6M in THF, 3.5 ml, 5.5 mmol) was added to a stirredsolution of 2-methylthiazole (0.45 ml, 5.0 mmol) in THF (15 mL) at −78°C. The reaction mixture was stirred at −78° C. for 40 min.Chlorotrimethylstannane (1M in THF, 5.0 ml, 5.0 mmol) was added.Stirring was continued at −78° C. for 45 min. The reaction mixture wasquenched with a satured aqueous solution of NaHCO₃. The aqueous layerwas extracted with Et₂O. The organic extracts were dried over MgSO₄,filtered and concentrated in vacuo. Used in the next step withoutpurification (obtained 1.29 g). MS m/z=264.1. Calc'd for C ,7; H, 13; N,S, Sn: 261.94.

2) Preparation of4-((8-fluoro-6-(2-methylthiazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-methoxyquinoline

Prepared by a method similar to4-((8-fluoro-6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-methoxyquinoline.MS m/z=422.1 [M+H]⁺. Calc'd for C, 21; H, 16; FN, 5; O, 2; S: 421.46

EXAMPLE 87N,N-dimethyl-3-(4-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)pyridin-3-yl)prop-2-yn-1-amine 1)Preparation of3-((3-iodopyridin-4-yloxy)methyl)-6-phenyl-[1,2,4]triazolo[4,3-b]pyridazine

Cesium carbonate (354 mg, 1087 μmol) was added to a mixture of(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanol (123 mg, 544μmol) (named 77289-19-99) and(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanol (123 mg, 544μmol) in DMSO (1.8 mL). The reaction mixture was stirred at 120° C. for2 h under micro-waves irradiation. The reaction mixture was diluted withEtOAc. The organic layer was washed with water. The water layerextracted with EtOAc. The organic layer was dried over MgSO₄, filteredand concentrated in vacuo. Purification by MPLC afforded the titlecompound (161 mg, 69% yield).

2) Preparation ofN,N-dimethyl-3-(4-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)pyridin-3-yl)prop-2-yn-1-amine

Tetrakis(triphenylphosphine)palladium(0) (14.4 mg, 12.5 μmol) was addedto a suspension of3-((3-iodopyridin-4-yloxy)methyl)-6-phenyl-[1,2,4]triazolo[4,3-b]pyridazine(107 mg, 249 μmol) and 1-dimethylamino-2-propyne (80.4 μl, 748 μmol) inTHF (0.6 mL) and triethylamine (591 μl, 4238 μmol) at RT. Copper(i)iodide, 99.999% (4.75 mg, 24.9 μmol) was added and the reaction mixturewas stirred at 75° C. (oil bath) for ˜75 min. The reaction mixture wascooled at RT, concentrated in vacuo. Purification by MPLC (ISCO,CH₂Cl₂/MeOH: 100/0 to 90/10) afforded the title compound. MS m/z=385.1[M+H]⁺. Calc'd for C, 22; H, 20; N, 6; O, : 384.44

EXAMPLE 88

Preparation of3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile

4-((6-Bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-methoxyquinolinewas prepared as previously described in general Method A.

4-((6-Bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-methoxyquinoline(0.050 g, 0.13 mmol) was dissolved in DMF (1 mL) then added zinc cyanide(0.023 g, 0.19 mmol), 1,1′-bis(diphenylphosphino)ferrocene (0.0072 g,0.013 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.0059 g,0.0065 mmol). The reaction mixture was heated at 100° C. for 8 hours.Additional zinc cyanide (0.012 g, 0.095 mmol),1,1′-bis(diphenylphosphino)ferrocene (0.004 g, 0.0065 mmol) andtris(dibenzylideneacetone)dipalladium(0) (0.003 g, 0.0032 mmol) wereadded and heating was continued at 100° C. for 6 hours. The reactionmixture was concentrated under vacuum. The sample was purified bypreparative TLC eluting with 10% 7N ammonia in methanol/dichloromethaneto afford3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile(23 mg, 53% yield) as a white solid.

MS (ESI pos. ion) m/z: 332.1 (MH⁺).

EXAMPLE 89

Preparation of3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide3-((7-Methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrilewas prepared as previously described.

3-((7-Methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile(0.050 g, 0.15 mmol) was dissolved in concentrated sulfuric acid (0.5mL). The reaction mixture was heated at 50° C. for 30 minutes. Thereaction mixture was slowly poured in to cold saturated aqueous sodiumbicarbonate. A precipitate formed which was collected on a glass frit,washing with water. The solid was transferred withdichlororethane/methanol to a flask and dried under high vacuum toafford3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide(0.050 g, 95% yield) as a tan solid.

MS (ESI pos. ion) m/z: 350.2 (MH⁺).

EXAMPLE 90

Preparation of3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylicacid3-((7-Methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrilewas prepared as previously described.

3-((7-Methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile(0.050 g, 0.15 mmol) was dissolved in concentrated sulfuric acid (0.375mL) and water (0.125 mL). The reaction mixture was heated at 100° C. for3.5 hours then slowly poured in to ice. The mixture was adjusted toapprox. pH 7 with saturated aqueous sodium carbonate. A precipitateformed which was collected on a glass frit, washing with water. Thesolid was dried under high vacuum to afford3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylicacid (0.047 g, 89% yield) as a tan solid.

MS (ESI pos. ion) m/z: 351.1 (MH⁺).

Preparation ofN-cyclopropyl-3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide.3-((7-Methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylicacid (0.047 g, 0.13 mmol), cyclopropanamine (0.011 ml, 0.16 mmol),1-hydroxy-7-azabenzotriazole (0.018 g, 0.13 mmol), andN-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride, (0.039 g,0.20 mmol) were added to a reaction flask then suspended in DMF (1 mL).N-Ethyldiisopropylamine (0.070 ml, 0.40 mmol) was added to the reactionmixture. The clear reaction mixture was stirred at 20° C. overnight. Thereaction mixture was concentrated under vacuum then triturated withwater. The solid was collected on a glass frit, washing with water. Thesample was purified by preparative TLC eluting with 8% 7N ammonia inmethanol/dichloromethane to affordN-cyclopropyl-3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide(0.023 g, 44% yield) as a tan solid.

MS (ESI pos. ion) m/z: 390.2 (MH⁺).

EXAMPLE 91

Preparation of7-methoxy-4-((6-(1,2,3,6-tetrahydropyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)quinoline

tert-Butyl4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylatewas prepared as described in general Method A.

tert-Butyl4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate(0.113 g, 0.23 mmol) was dissolved in methanol (3 mL) then addedconcentrated hydrochloric acid (0.500 ml, 6.0 mmol). The reactionmixture was stirred at room temperature overnight then concentratedunder vacuum. The remaining solid was suspended in methanol (1 mL) thenadded triethylamine (0.40 ml, 2.9 mmol). The clear solution was stirredat room temperature for 2 hours then concentrated under vacuum. Thesample was purified by flash chromatography eluting with 8% 7N ammoniain methanol/dichloromethane to afford7-methoxy-4-((6-(1,2,3,6-tetrahydropyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)quinoline(0.038 g, 42% yield) as a tan solid.

MS (ESI pos. ion) m/z: 388.1 (MH⁺).

EXAMPLE 92

Preparation of(S)-3-((7-methoxyquinolin-4-yloxy)methyl)-N-(pyrrolidin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide

(S)-tert-Butyl3-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamido)pyrrolidine-1-carboxylatewas prepared as previously described forN-cyclopropyl-3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide.

(S)-tert-Butyl3-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamido)pyrrolidine-1-carboxylate(0.050 g, 0.096 mmol) was dissolved in methanol (1.5 mL) then addedconcentrated hydrochloric acid (0.400 ml, 4.8 mmol). The reactionmixture was stirred at room temperature for 5 hours then concentratedunder vacuum. The remaining solid was dissolved in methanol (1 mL) thenadded potassium carbonate (0.062 g, 0.45 mmol). The reaction mixture wasstirred at room temperature for 1 hour and concentrated under vacuum.The sample was purified by flash chromatography eluting with 10%-15% 7Nammonia in methanol/dichloromethane to afford(S)-3-((7-methoxyquinolin-4-yloxy)methyl)-N-(pyrrolidin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide(0.039 g, 97% yield) as a pale yellow solid.

MS (ESI pos. ion) m/z: 419.2 (MH⁺).

EXAMPLE 93(R)-3-((7-Methoxyquinolin-4-yloxy)methyl)-N-(pyrrolidin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamidewas prepared as previously described for(S)-3-((7-methoxyquinolin-4-yloxy)methyl)-N-(pyrrolidin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide.

EXAMPLE 94

N-Ethyl-3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamidewas prepared as previously described forN-cyclopropyl-3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide.

EXAMPLE 95

Preparation of tert-butyl2-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamido)ethyl(methyl)carbamate

3-((7-Methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylicacid was prepared as previously described.

3-((7-Methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylicacid (0.072 g, 0.21 mmol) was dissolved in DMF (1.5 mL) then addedN-(2-aminoethyl)-N-methyl carbamic acid tert-butyl ester (0.054 ml, 0.31mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (0.12 g, 0.31 mmol) and triethylamine (0.043 ml,0.31 mmol). The reaction mixture was stirred at room temperatureovernight then concentrated under vacuum. The sample was purified byflash chromatography eluting with 6% 7N ammonia inmethanol/dichloromethane to afford tert-butyl2-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamido)ethyl(methyl)carbamate(0.097 g, 93% yield) as a pale yellow solid.

MS (ESI pos. ion) m/z: 507.3 (MH⁺).

Preparation of3-((7-methoxyquinolin-4-yloxy)methyl)-N-(2-(methylamino)ethyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide

tert-Butyl2-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamido)ethyl(methyl)carbamatewas deprotected as previously described for7-methoxy-4-((6-(1,2,3,6-tetrahydropyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)quinoline.

EXAMPLE 96

3-((7-Methoxyquinolin-4-yloxy)methyl)-N-phenyl-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamidewas prepared as described for3-((7-methoxyquinolin-4-yloxy)methyl)-N-(2-(methylamino)ethyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide.

EXAMPLE 97

N-(4-Fluorophenyl)-3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamidewas prepared as described for3-((7-methoxyquinolin-4-yloxy)methyl)-N-(2-(methylamino)ethyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide.

EXAMPLE 98

N-(3-Fluorophenyl)-3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamidewas prepared as described for3-((7-methoxyquinolin-4-yloxy)methyl)-N-(2-(methylamino)ethyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide.

(4-bromo-2-chlorophenyl)methanamine. To a solution of4-bromo-2-chlorobenzonitrile (2500 mg, 11549 μmol) in THF (20 mL) at 0°C. was added borane-methyl sulfide complex, 2.0 m sol in THF (28873 μl,57747 μmol). Ice bath removed and reaction stirred overnight warming to23° C. Reaction cooled to 0° C. and quenched with MeOH (15 mL). Reactionthen partitioned between CHCl₃ (100 mL) and 1M NaOH (100 mL). Organicdried with brine and MgSO₄. Organic then concentrated to an oil underreduced pressure and purified on silica (80 g) eluting with 0>6% 2M NH₃in MeOH/DCM and product isolated as a colorless oil. MS (ESI pos. ion)m/z: 220/222 (MH+). Calc'd exact mass for C₇H₇BrClN: 219/221

tert-butyl 4-bromo-2-chlorobenzylcarbamate. To a stirring solution of(4-bromo-2-chlorophenyl)methanamine (2200 mg, 9978 μmol) in DCM (10 mL)was added BOC-Anhydride (9978 μl, 9978 μmol) [1M in THF] and stirred for1 h at 23° C. after which ethylenediamine (1 mL) added. Solvents removedunder reduce pressure and residue purified on 80 g silica elutingproduct with 0>50% Hex/EtOAc.

tert-butyl2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate.A suspension of tert-butyl 4-bromo-2-chlorobenzylcarbamate (1670 mg,5209 μmol), bis(pinacolato)diboron (1455 mg, 5730 μmol),dichloro[1,1′bis(diphenylphoshino)ferrocene]palladium(ii)dichloromethaneadduct (190.6 mg, 260.4 μmol), and potassium acetate (1022 mg, 10418μmol) in dioxane (8 mL) was sparged with argon for 5 min then heated to120° C. in an appropriately sealed vial with stirring. After 1 h,reaction partitioned between DCM (50 mL) and 5% NaHCO3 (25 mL). Organicdried over MgSO4, concentrated, then purified on 80 g silica elutingwith 0>40% EtOAc/hexanes and product isolated as a viscous amber oil.

(4-bromo-2-chlorophenyl)methanol. To a stirring solution of4-bromo-2-chlorobenzoic acid (11.1 g, 47 mmol) in THF (100 mL) at 0° C.under nitrogen was added borane-methyl sulfide complex (9.4 ml, 94 mmol)via syringe over 10 min. Gas evolution quite evident. Ice bath removed,and once gas evolution subsided reaction gently heated to reflux for 1h. Reaction slowly quenched with MeOH (50 mL) and 2M HCl (20 mL).Aqueous extracted with 9:1 CHCl₃/IPA (150 mL). Organic dried with satNH₄Cl, MgSO₄, then concentrated to a colorless oil under reducedpressure. Product crystallized after 1 week sitting neat.

(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl). Asuspension of (4-bromo-2-chlorophenyl)methanol (1000 mg, 4515 μmol),bis(pinacolato)diboron (1261 mg, 4967 μmol),dichloro[1,1′bis(diphenylphoshino)ferrocene]palladium(ii)dichloromethaneadduct (165.2 mg, 225.8 μmol), and potassium acetate (886.2 mg, 9030μmol) in dioxane (5 mL) was sparged with argon for 10 min then heated to120° C. with stirring in an appropriately sealed vial. After 1 h,reaction then partioned between DCM (50 mL) and 5% NaHCO₃ (20 mL).Organic dried over MgSO₄, concentrated, then purified on 80 g silicaeluting with 0>70% EtOAc/Hex. Product isolated as a light amber oil.

To a stirring solution of 4-bromo-2-chlorobenzoic acid (3.45 g, 15 mmol)and DIEA (7.7 ml, 44 mmol) in DMF (30 mL) was added HATU (6.1 g, 16mmol) at 23° C. under nitrogen. Darkened suspension stirred for 1 h,then added n,o-dimethylhydroxyl amine hydrochloride (2.1 g, 22 mmol).Solution stirred overnight at 23° C. Reaction then partitioned between2.5% NaHCO₃ (250 mL) and diethyl ether (100 mL). Aqueous furtherextracted with ether (2×50 mL). Combined ethereal extracts dried overMgSO₄, then concentrated an amber oil under reduced pressure.4-bromo-2-chloro-N-methoxy-N-methylbenzamide isolated as a light amberoil.

1-(4-bromo-2-chlorophenyl)ethanone. To a stirring solution of4-bromo-2-chloro-N-methoxy-N-methylbenzamide (890 mg, 3195 μmol) in THF(10 mL) at −5° C. under nitrogen was slowly added methylmagnesiumbromide 3.0 m in diethyl ether (1278 μl, 3834 μmol). After 30 minanother 1.3 mL (3.8 mmol; 1.2 eq) of MeMgBr added at 23° C. After anadditional hour, LCMS suggests 95% conversion. Reaction quenched withsat NH₄Cl (10 mL) and resulting white cake washed repeatedly withdiethyl ether. Combined organics washed with water and sat NaCl thenpushed through a plug of silica (10 g).1-(4-bromo-2-chlorophenyl)ethanone isolated as a colorless oil.

1-(4-bromo-2-chlorophenyl)ethanol. To a stirring solution of1-(4-bromo-2-chlorophenyl)ethanone (700 mg, 2998 μmol) in THF (20 mL)was added sodium borohydride (340 mg, 8994 μmol) and methanol (5 mL).Reaction suspension stirred overnight at 30° C. Reaction then partionedbetween EtOAc (50 mL) and sat NH₄Cl (25 mL). Aqueous further extractedwith EtOAc (2×25 mL). Combined organics dried over MgSO₄, concentrated,then purified on silica (40 g) eluting with 10>40% EtOAc/hexanes.Product isolated as a colorless oil.

1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanol.A suspension of 1-(4-bromo-2-chlorophenyl)ethanol (600 mg, 2548 μmol),bis(pinacolato)diboron (712 mg, 2802 μmol),dichloro[1,1′bis(diphenylphoshino)ferrocene]palladium(ii)dichloromethaneadduct (93.2 mg, 127 μmol), potassium acetate (319 μl, 5095 μmol) indioxane (5 mL) was sparged with argon for 5 min then heated to 120° C.in an appropriately sealed vial. Reaction then partitioned between EtOAc(25 mL) and 5% NaHCO₃ (25 mL). Aqueous further washed with EtOAc (2×20mL). Combined organics dried with sat NH₄Cl, MgSO₄, concentrated, thenpurified on silica (80 g) eluting with 10>35% EtOAc/Hex. Productisolated as a colorless oil.

4-bromo-2-chlorobenzaldehyde. To a stirring solution of(4-bromo-2-chlorophenyl)methanol (4.5 g, 20 mmol) in DCM (50 mL) wasadded Dess-Martin periodinane (9.3 g) at 23° C. Reaction refluxed afteraddition. After 20 min, TLC (1:4 EtOAc/Hex) suggests full conversion ofalcohol. Suspension then washed with 5% NaHCO₃ (100 mL plus 15 g dryNaHCO₃). Organic dried over MgSO₄, concentrated onto dry silica (15 g),then purified on silica (120 g) eluting with 0>10% EtOAc/hex.4-bromo-2-chlorobenzaldehyde isolated as a white solid.

1-(4-bromo-2-chlorophenyl)ethanamine. A solution of1-(4-bromo-2-chlorophenyl)ethanone (2.430 g, 10 mmol), ammonia, 2.0 msolution in methanol (26 ml, 52 mmol) and titanium (iv) isopropoxide (6ml, 21 mmol) was stirred for 16 h in a sealed vessel. Reaction thenadded to a freshly made suspension of sodium borohydride powder, 98% (4g, 104 mmol) in MeOH (20 mL). Exothermic reaction started at 9:45 am,then continued to stir with a 45° C. external heating bath for 45 min.Water (10 mL) then added to reaction and stirred for an additional 10min. Resulting white solid removed via filtration through Celite, andfiltrated reduced in volume under reduced pressure. This suspension thenpartioned between 9:1 CHCl₃/IPA (30 mL) and 1M NaOH (10 mL). Aqueousfurther extracted with 9:1 CHCl₃/IPA (2×10 mL). Combined organics driedover MgSO₄, concentrated, then purified on silica (80 g) eluting with0>5% 2M NH₃ in MeOH/DCM. MS (ESI pos. ion) m/z: 234/236 (MH+). Calc'dexact mass for C₈H₉BrClN: 233/235. 1-(4-bromo-2-chlorophenyl)ethanamineisolated as a colorless oil.

tert-butyl1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethylcarbamate.To a stirring solution of 1-(4-bromo-2-chlorophenyl)ethanamine (950 mg,4051 μmol) in DCM (5 mL) was added BOC-anhydride (4861 μl, 4861 μmol)[1M in THF]. Reaction stirred for 18 h at 23° C. Ethanolamine (0.25 mL)added and stirred for 5 min. Reaction then partitioned between diethylether (50 mL) and 5% NaHCO₃ (25 mL). Organic dried over MgSO₄,concentrated, then purified on silica (80 g) eluting with 0>20%EtOAc/hexanes. BOC-1.10 g. A suspension of the Bromo-BOC intermediate,bis(pinacolato)diboron (1132 mg, 4456 μmol),dichloro[1,1′bis(diphenylphoshino)ferrocene]palladium(ii)dichloromethaneadduct (148 mg, 203 μmol), and potassium acetate (795 mg, 8102 μmol) indioxane (8 mL) was sparged with argon for 5 min then heated to 120° C.in an appropriately sealed vessel for 2 h. Reaction then partitionedbetween 9:1 CHCl₃/IPA (50 mL) and sat. NH₄Cl (20 mL). Organic dried overMgSO₄, concentrated, and product purified on silica (80 g) eluting with10>15% of EtOAc/Hex. tert-butyl1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethylcarbamateisolated as a white foam.

(R,Z)-N-(4-bromo-2-chlorobenzylidene)-2-methylpropane-2-sulfinamide. Asuspension of 4-bromo-2-chlorobenzaldehyde (1150 mg, 5240 μmol),(r)-(+)-2-methyl-2-propanesulfinamide (1588 mg, 13100 μmol), copper(ii)sulfate (696.4 μl, 15720 μmol) in DCM (10 mL) was stirred at 37° C. for78 h. Reaction filtered through Celite, and solid washed repeatedly withDCM. Filtrate concentrated then purified on silica (80 g) elutingproduct with 0>30% of EtOAc/Hex. MS (ESI pos. ion) m/z: 322/324 (MH+).Calc'd exact mass for C₁₁H₁₃BrClNOS: 321/323.

(R)-N-((S)-1-(4-bromo-2-chlorophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide.To a stirring solution of(R,Z)-N-(4-bromo-2-chlorobenzylidene)-2-methylpropane-2-sulfinamide(1370 mg, 4246 μmol) and (trifluoromethyl)trimethylsilane (943 μl, 6369μmol) in DMF (5 mL) was added 1,3-bis(1-adamantyl)imidazol-2-ylidene(143 mg, 425 μmol). Reaction stirred at 35° C. for 18 h then quenchedwith sat NH₄Cl (10 mL). Reaction partitioned between EtOAc (40 mL) and5% NaHCO₃ (10 mL). Organic dried over MgSO4, concentrated to and oilfrom toluene, then purified on silica (80 g) eluting with 20>30%EtOAc/Hex. Product isolated as a white solid.

(R)-N-((S)-1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide.A suspension of(R)-N-((S)-1-(4-bromo-2-chlorophenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide(950 mg, 2419 μmol); bis(pinacolato)diboron (676 mg, 2661 μmol),dichloro[1,1′bis(diphenylphoshino)ferrocene]palladium(ii)dichloromethaneadduct (88.5 mg, 121 μmol), and potassium acetate (475 mg, 4839 μmol) indioxane (6 mL) was sparged with argon for 5 min. Reaction thenappropriately sealed and heated to 120° C. with stirring for 1 h.Reaction then partitioned between EtOAc (25 mL) and 5% NaHCO₃ (10 mL).Organic dried over MgSO₄, concentrated, then purified on silica (120 g)eluting product with 10>20% of EtOAc/hexanes. Product isolated as a waxywhite solid. MS (ESI pos. ion) m/z: 440 (MH+). Calc'd exact mass forC₁₈H₂₆BClF₃NO₃S: 439.

EXAMPLE 99

(2-chloro-4-(3-(quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)methanol.A suspension of6-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline (170mg, 575 μmol),(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol(309 mg, 1150 μmol),dichloro[1,1′bis(diphenylphoshino)ferrocene]palladium(ii)dichloromethaneadduct (126 mg, 172 μmol), cesium carbonate (749 mg, 2299 μmol) inDioxane (0.3 mL) and water (0.3 mL) was sparged with argon for 5 minthen heated to 100° C. with stirring. 1:30 am. After 90 min, LCMSsuggests 95% conversion. Reaction then partitioned between 9:1 CHCl₃/IPA(25 mL) and 5% NaHCO₃ (15 mL). Aqueous further extracted with 9:1CHCl₃/IPA (2×10 mL). Combined organics dried with MgSO₄, concentratedonto dry silica (10 g), and then purified on silica (12 g) eluting with0>10% 2M NH₃ in MeOH/DCM. Resulting solid triturated with methanol (2mL) and collected by filtration. MS (ESI pos. ion) m/z: 402 (MH+).Calc'd exact mass for C₂₂H₁₆ClN₅O: 401.

EXAMPLE 100

(2-chloro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)methanol.A suspension of4-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline(200 mg, 585 μmol),(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol(173 mg, 644 μmol),dichloro[1,1′bis(diphenylphoshino)ferrocene]palladium(ii)dichloromethaneadduct (21 mg, 29 μmol), and sodium carbonate (2M; 1170 μl, 2341 μmol)in DME (2 mL) was sparged with argon for 10 min then heated to 85° C.for 6 h. Reaction then partitioned between 9:1 CHCl₃/IPA (25 mL) and 5%NaHCO₃ (10 mL) and aqueous further extracted with 9:1 CHCl₃/IPA (2×10mL). Combined organics dried with MgSO₄ then concentrated onto drysilica under reduced pressure. Product purified on 40 g silica elutingwith 0>12% of 2M NH₃ in MeOH/DCM and isolated as an off white powder. MS(ESI pos. ion) m/z: 448 (MH+). Calc'd exact mass for C₂₃H₁₈ClN₅O₃: 447.

EXAMPLE 101

1-(2-chloro-4-(3-((7-methoxy-1,5-naphthyridin-4-ylamino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)ethanol.A suspension of1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanol(228 mg, 807 μmol),N-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine(197 mg, 576 μmol), dichloro[1,1bis(diphenylphoshino)ferrocene]palladium(ii)dichloromethane adduct (127mg, 173 μmol), cesium carbonate (751 mg, 2306 μmol) in dioxane (3 mL)and water (0.6 mL) was sparged with argon for 5 min then heated to 100°C. for 6 h. Reaction cooled then partitioned between 9:1 CHCl₃/IPA (20mL) and 1M NaOH (15 mL). Aqueous further extracted with 9:1 CHCl₃/IPA(2×10 mL). The combined organics dried over MgSO₄. concentrated, thenpurified on 40 g silica eluting with an isocratic 7% 2M NH₃ in MeOH/DCM.Product further purified prep HPLC eluting with water/ACN (0.1% TFA).After collected fractions were reduced to a clear the residue wasdissolved in 1:1 ACN/water and pH adjusted to 9 with 1M NaOH (3-4drops). Resulting solid collected by filtration and solid washed withwater (2 mL). MS (ESI pos. ion) m/z: 462 (MH+). Calc'd exact mass forC₂₃H₂₀ClN₇O₂: 461.

EXAMPLE 102

tert-butyl(2-chloro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)methylcarbamate.A suspension of4-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline(200 mg, 585 μmol), tert-butyl2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate(323 mg, 878 μmol), dichloro[1,1bis(diphenylphoshino)ferrocene]palladium(ii)dichloromethane adduct (86mg, 117 μmol), cesium carbonate (763 mg, 2341 μmol) in dioxane (3 mL)and water (0.3 mL) was sparged with argon for 10 min then heated to 100°C. for 18 h. Reaction then partitioned between 9:1 CHCl3/IPA (50 mL) and5% NaHCO₃ (25 mL). Aqueous further extracted with 9:1 CHCl3/IPA (2×10mL). Combined organics then dried over MgSO₄, concentrated, and purifiedon silica (40 g) eluting with 0>6% 2M NH₃ in MeOH/DCM. Product isolatedas an off white solid. 84024-19-2 MS (ESI pos. ion) m/z: 547 (MH+).Calc'd exact mass for C₂₈H₂₇ClN₆O₄: 546.

EXAMPLE 103

2-chloro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)methanamine.A solution of tert-butyl(2-chloro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)methylcarbamate(85 mg, 155 μmol) in DCM (2 mL) and TFA (2 mL) stirred for 30 min at 23°C. Solvents removed under reduced pressure, then residue partitionedbetween 9:1 DCM/IPA (10 mL) and 1M NaOH (5 mL). Aqueous furtherextracted with DCM (2×5 mL). Combined organics dried over MgSO₄, thenreduced to an off white solid under reduced pressure. MS (ESI pos. ion)m/z: 447 (MH+). Calc'd exact mass for C₂₃H₁₉ClN₆O₂: 446.

EXAMPLE 104(S)-1-(2-chloro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)-2,2,2-trifluoroethanamine

A solution of(R)-N-((S)-1-(2-chloro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide(135 mg, 218 μmol) in MeOH (2 mL) and 4M HCl (2 mL) was stirred for 30min at 35° C. LCMS suggests full conversion. Solvents removed underreduced pressure with azeotroping from toluene. Residue dissolved inMeOH (10 mL) and Si-Carbonate (2 g; 1.4 mmol) added. Suspension stirredfor 30 min, then filtrated collected by filtration. Solvents removedunder reduced pressure and residue purified on silica (12 g) elutingproduct with 0>5% MeOH/DCM. MS (ESI pos. ion) m/z: 515 (MH+). Calc'dexact mass for C₂₄H₁₈ClF₃N₆O₂: 514.

EXAMPLE 105(R)-1-(2-chloro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)-2,2,2-trifluoroethanamine

A solution of(S)-N-((R)-1-(2-chloro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide(62 mg, 100 μmol) in MeOH (2 mL) and 5M HCl (2 mL) was stirred at 35° C.for 18 h. LCMS suggests full conversion. Solvents removed under reducedpressure and residue dissolved in MeOH (20 mL). Si-Carbonate (1.3 g; 0.9mmol) added to solution and stirred for 2 h. Filtrated isolated byfiltration and reduced to a film under reduced pressure. Productpurified on silica (4 g) eluting with 7% 2M NH₃ in MeOH/DCM. MS (ESIpos. ion) m/z: 515 (MH+). Calc'd exact mass for C₂₄H₁₈ClF₃N₆O₂: 514.

EXAMPLE 106

tert-butyl1-(2-chloro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)ethylcarbamate.A suspension of4-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline(180 mg, 527 μmol), tert-butyl1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethylcarbamate(302 mg, 790 μmol), dichloro[1,1bis(diphenylphoshino)ferrocene]palladium(ii)dichloromethane adduct (77.1mg, 105 μmol), cesium carbonate (686 mg, 2107 μmol) in DMF (2 mL) andwater (0.4 mL) was first sparged with argon for 5 min then heated to100° C. with stirring. 2:20 pm After 10 min, LCMS suggests >95%conversion. Reaction then partitioned between 9:1 CHCl₃/IPA (20 mL) and1M NaOH (5 mL). Organic then dried over MgSO4, concentrated, andpurified on silica (40 g) eluting with isocratic 4% of 2M NH₃ inMeOH/DCM. MS (ESI pos. ion) m/z: 561 (MH+). Calc'd exact mass forC₂₉H₂₉ClN₆O₄: 560.

EXAMPLE 107

1-(2-chloro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)ethanamine.A solution of tert-butyl1-(2-chloro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)ethylcarbamate(100 mg, 178 μmol) in DCM (2 mL) and TFA (2 mL) was stirred for 30 minat 23° C. Solvents removed under reduced pressure (not-tolueneazeotroping is suggested!) and residue dissolved in CHCl₃/IPA (10 mL).Solution stirred as a suspension with Si-Carbonate (1.3 g; 1 mmol) for30 min. Suspension filtered and filtrate reduced to an amber film (150mg). Product purified on silica (12 g) eluting with 4-7% of 2M NH₃ inMeOH/DCM. MS (ESI pos. ion) m/z: 461 (MH+). Calc'd exact mass forC₂₄H₂₁ClN₆O₂: 460.

EXAMPLE 108

N-((6-(4-(aminomethyl)-3-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine.To a stirring solution of tert-butyl(2-chloro-4-(3-((7-methoxy-1,5-naphthyridin-4-ylamino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)methylcarbamate(70 mg, 128 μmol) in DCM (2 mL) was added TFA (2 mL). Reaction solutionstirred for 30 min at 23° C. Solvents then removed under reducedpressure and residue purified on prep-HPLC using a water/ACN (0.1% TFA)gradient. Resulting solid was dissolved in 1:1 ACN/water (1 mL) and pHadjusted to 10 with 1M NaOH (approx 10 drops). Resulting solid collectedby filtration and washed with water (5 mL). MS (ESI pos. ion) m/z: 447(MH+). Calc'd exact mass for C₂₂H₁₉ClN₈O: 446.

methyl 2-(3-methoxyquinolin-6-yl)-2-methylpropanoate. To a stirringsolution of methyl 2-(3-methoxyquinolin-6-yl)acetate (450 mg, 1946 μmol)in THF (5 mL) at −70° C. under nitrogen was added lithiumbis(trimethylsilyl)amide, 1.0 m solution in tetrahydrofuran (5838 μl,5838 μmol). Dark red solution stirred for 10 min, then added iodomethane(364 μl, 5838 μmol) in THF (1 mL). Reaction removed from cooling bath,and monitored by LCMS after 45 min. LCMS suggests very clean conversion.Reaction quenched with sat NH₄Cl (5 mL) and NaHCO₃ (5 mL). Aqueousextracted with EtOAc (3×40 mL). Combined organics dried over MgSO4,concentrated, then purified on silica (40 g) eluting with 10>30% ofEtOAc/Hex. MS (ESI pos. ion) m/z: 260 (MH+). Calc'd exact mass forC₁₅H₁₇NO₃: 259.

2-(3-methoxyquinolin-6-yl)-2-methylpropanoic acid. A solution of methyl2-(3-methoxyquinolin-6-yl)-2-methylpropanoate (400 mg, 1543 μmol), LiOH(1928 μl, 7713 μmol) [4M], MeOH (2 mL), and THF (2 mL) was stirred at50° C. overnight. LCMS suggests full conversion. Solution cooled,acidified to pH 1 with 5M HCl, and precipitate collected by filtration.White cake washed with water (2 mL) and EtOH (1 mL). Product air driedfor 3 h and isolated as a white solid. MS (ESI pos. ion) m/z: 246 (MH+).Calc'd exact mass for C₁₄H₁₅NO₃: 245.

2-(3-methoxyquinolin-6-yl)-2-methyl-N′-(6-phenylpyridazin-3-yl)propanehydrazide.A suspension of 2-(3-methoxyquinolin-6-yl)-2-methylpropanoic acid (92mg, 375 μmol), DIEA (66 μl, 375 μmol), ando-(7-azabenzotriazol-1-yl)-n,n,n′,n-tetramethyl uroniumhexafluorophosphate (143 mg, 375 μmol) in DMF was stirred for 2 h at 23°C. To the solution was added 1-(6-phenylpyridazin-3-yl)hydrazine (70 mg,375 μmol) and stirred for 72 h at 23° C. Reaction partitioned between9:1 CHCl3/IPA (25 mL) and 1M NaOH (5 mL). Organic dried over MgSO₄ theconcentrated to a solid from toluene under reduced pressure. Solidtriturated with ACN (2 mL) and collected by filtration.2-(3-methoxyquinolin-6-yl)-2-methyl-N′-(6-phenylpyridazin-3-yl)propanehydrazideisolated as a white solid. MS (ESI pos. ion) m/z: 414 (MH+). Calc'dexact mass for C₂₄H₂₃N₅O₂: 413.

EXAMPLE 1093-methoxy-6-(2-(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)propan-2-yl)quinoline

A solution of2-(3-methoxyquinolin-6-yl)-2-methyl-N′-(6-phenylpyridazin-3-yl)propanehydrazide(270 mg, 653 μmol) in TFA (2 mL) was heated to 150° C. in microwave (6bar; 20 W) for 2 h. LCMS suggests very good conversion: 89425-17-1.Reaction concentrated under reduced pressure then partitioned betweenCHCl₃/IPA (50 mL) and 1M NaOH (50 mL). Aqueous further extracted withCHCl₃/IPA (15 mL) and combined organics dried over MgSO₄, concentrated,then dissolved in ACN (2 mL). Crystallized solid washed with ACN (1 mL)and dried under reduced pressure. MS (ESI pos. ion) m/z: 396 (MH+).Calc'd exact mass for C₂₄H₂₁N₅O: 395.

EXAMPLE 110

6-(1-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline. Asolution ofN′-(6-chloropyridazin-3-yl)-2-(quinolin-6-yl)propanehydrazide (4300 mg,13119 μmol) in TFA (40 mL) was heated to 120° C. with microwaves for 40min. LCMS suggests very good conversion. Solvents removed under reducedpressure and residue partitioned between 9:1 CHCl₃/IPA (75 mL) and 1MNaOH (100 mL). Aqueous further extracted with 9:1 CHCl₃/IPA (2×25 mL).Combined organics dried over MgSO4, concentrated, and oily residuedissolved in ACN/MeOH (2 mL). Resulting solid after 2 h was isolated byfiltration and washed with ACN (5 mL).6-(1-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinolineisolated as a white solid. MS (ESI pos. ion) m/z: 310 (MH+). Calc'dexact mass for C₁₆H₁₂ClN₅: 309.

EXAMPLE 111

6-(1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline.A suspension of6-(1-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline (106mg, 342 μmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(142 mg, 684 μmol),dichloro[1,1′bis(diphenylphoshino)ferrocene]palladium(ii)dichloromethaneadduct (25 mg, 34 μmol), and cesium carbonate (446 mg, 1369 μmol) in DMF(1 mL) and water (0.5 mL) was sparged for 5 min with argon then heatedto 100° C. in an appropriately sealed vial for 30 min. Reaction thenpartitioned between 9:1 CHCl₃/IPA (20 mL) and 1M NaOH (5 mL). Aqueousfurther extracted with 9:1 CHCl₃/IPA (5 mL) and combined organics driedover MgSO4, concentrated to a solid from toluene, then purified onsilica (12 g) eluting with 30>50% of 10% 2M NH₃ in MeOH/DCM.6-(1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinolineisolated as off white crystals from ACN (1 mL). MS (ESI pos. ion) m/z:356 (MH+). Calc'd exact mass for C₂₀H₁₇N₇: 355.

EXAMPLE 112

3-(6-(3,5-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)quinoline.To a mixture of quinolin-3-ol (0.058 g, 0.40 mmol),(6-(3,5-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanol(0.104 g, 0.4 mmol), and triphenylphosphine (0.11 g, 0.44 mmol) in drytetrahydrofuran (2 ml) and dry dichloromethane (2 ml) under argon, wasadded dropwise with stirring, diethyl azodicarboxylate (0.069 ml, 0.44mmol). The resulting mixture was stirred at room temperature for 18hours. The solvent was then stripped at reduced pressure, and theresidue subjected to chromatography on Silica gel, eluent 5% methanol indichloromethane to afford the title compound, which was recrystallisedfrom hot toluene to give a colourless solid. M/e 390 (MH⁺)

EXAMPLE 113

N-((6-(4-(1-aminoethyl)-3-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy)-1,5-naphthyridin-4-amine.A suspension ofN-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine(300 mg, 878 μmol), tert-butyl1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethylcarbamate(419 mg, 1097 μmol),dichloro[1,1′bis(diphenylphoshino)ferrocene]palladium(ii)dichloromethaneadduct (193 mg, 263 μmol), cesium carbonate (1144 mg, 3511 μmol) indioxane (6 mL) and water (1 mL) was sparged with argon for 10 min thenheated to 100° C. for 20 h with stirring. Reaction then partitionedbetween 9:1 CHCl₃/IPA (50 mL) and 1M NaOH (25 mL). Aqueous furtherextracted with 9:1 CHCl₃/IPA (20 mL). Combined organics then dried overMgSO4, concentrated, and purified on 40 g silica eluting with 7>8% of 2MNH₃ in MeOH/DCM. Product then further purified on prep HPLC eluting withwater/ACN (0.1% TFA). BOC intermediate then stirred as a solution in DCM(1 mL) and TFA (3 mL) for 30 min. Solvents removed under reducedpressure and residue dissolved in MeOH (8 mL) and DCM (8 mL). Solutionthen stirred with Si-Carbonate from Silicycle (1 g/with a labeledloading of 0.77 mmol/g) for 1 h at 23° C. Suspension filtered andfiltrate reduced to a film under reduced pressure. Product waslyophilized from 1:1 ACN/water (1.5 mL) to provideN-((6-(4-(1-aminoethyl)-3-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy)-1,5-naphthyridin-4-amineas an off white fluffy solid. MS (ESI pos. ion) m/z: 461 (MH+). Calc'dexact mass for C₂₃H₂₁ClN₈O: 460.

EXAMPLE 114

6-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)isoquinoline

Step 1. tert-Butyl 2-(isoquinolin-6-yl)acetate. A dry, 25 mL, 1 neckround bottom flask was charged with a 0.5 M Et₂O solution of Zincate 2(10.00 ml, 5.0 mmol, Reike Metals), and concentrated in vacuo. Thevacuum was released with nitrogen, and the flask was charged with astirbar, 5 mL dry THF, fitted with a reflux condenser and an Ar inlet.Upon dissolution of the solids, 6-bromoisoquinoline (0.516 g, 2.5 mmol)and tetrakis(triphenylphosphine)palladium (0.24 g, 0.21 mmol) was added.The solution was heated with an 80° C. oil bath for 5 h, and cooled. Thesolution was treated with 30 mL of 10% aqueous EDTA (pH adjusted to 6.1with NaOH), and stirred for 1 h. A precipitate had formed that wasremoved by filtration of the biphasic solution through a sintered glassfunnel and discarded. The filtrate was concentrated to ˜35 mL, andextracted with DCM (4×30 mL). The combined extracts were washed withwater (1×30 mL), and the water was back-extracted with DCM (1×10 mL).The DCM layers were dried over MgSO₄, and the resultant slurry filteredthrough a sintered glass funnel. The filtrate was concentrated in vacuo.The residue was dissolved in 10 mL DCM and treated with Si-carbonate(Silicycle, 5.5 g, 3.7 mmol). The slurry was swirled occasionally for 1h, and filtered through a 0.22 uM PTFE membrane. The silica was washedwith DCM (4×20 mL), and the combined filtrates were concentrated invacuo. The residue was purified in three injections using a WatersSpherisorb S5 column (PN PSS830195, 20×250 mm, 60 Å pore, 5 μm particlesize); flow=20 mL/min; A=DCE, B=EtOH; isocratic at 5% B. A band thateluted from 3.9 to 5.9 minutes was isolated. The solvent was removed invacuo to afford tert-butyl 2-(isoquinolin-6-yl)acetate.

Step 2.6-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)isoquinolinehydrochloride. A 10 mL, CEM microwave vessel was charged with 3 (0.1040g, 0.427 mmol), 1-(5-phenylpyridin-2-yl)hydrazine (4, 0.119 g, 0.641mmol), a stirbar and 1 mL concentrated HCl. The vessel was sealed, andfitted with an 18-guage needle and an Argon inlet. The slurry was placedin a heating block at 115° C. for 15 minutes with stirring. A volatilesubstance evolved during this time. The vessel was briefly cooled, andthe seal was replaced. The vessel was irradiated on a CEM Explorer usingthe following parameters: ramp time 20 s, hold time 10 min, holdtemperature 150° C., powermax=on, 75 W max. The resultant turbid aqueoussolution was filtered and concentrated in vacuo. The solids weresuspended in 3 mL hot EtOH, and cooled. The precipitate was isolated byfiltration and washed with EtOH (3×3 mL). The solids were taken up in 2mL H₂O, and filtered through a 0.1 μm PVDF Ultra-free-C L centrifugalfilter (Millipore Corp, PN UFC40W00, 2000 g for 5 minutes). The aqueousfiltrate was lyophilized to afford6-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)isoquinolinehydrochloride. Anal. Calcd for C₂₁H₁₅N₅.HCl.1.7H₂O: C, 62.36; H, 4.83;N, 17.31. Found: C, 62.39±0.08; H, 4.48±0.02; N, 17.28±0.03.

EXAMPLE 115

8-((6-(3,4,5-trifluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylamino)-1,5-naphthyridin-3-ol.A sealed tube was charged with7-methoxy-N-((6-(3,4,5-trifluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-aminehydrochloride (238 mg, 502 μmol) and HBr (5966 μl, 52740 μmol), sealed,then placed in a 120° C. oil bath for 48 h. Cooled to room temperatureand brought to pH-14 with NaOH (6N). Isolated solid by filtration whichwas purified by RPHPLC to afford8-((6-(3,4,5-trifluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylamino)-1,5-naphthyridin-3-olas its formate salt. MS (ESI pos. ion) m/z: 424 (MH+). Calc'd exact massfor C₂₀H₁₂F₃N₇O: 423.

3-hydroxy-6-iodoquinoline-4-carboxylic acid. 5-iodoindoline-2,3-dione(50 g, 183 mmol) was dissolved in a hot solution containing potassiumhydroxide (82 g, 1465 mmol) and water (250 mL). The reaction mixture wasin homogeneous solution for 5 min then was precipitated out completely.Enough ethanol (30 ml) was added to redissolve the reaction mixture.After cooled to rt and mechanically stirred, 3-bromo-2-oxopropanoic acidhydrate (47 g, 256 mmol) was added portionwise—tremendous heat wasgenerated (>80° C.). After the addition, the reaction mixture was cooledto rt and continued to stir for 3 days. The reaction mixture was treatedwith sat. solution of NaHSO₃ (sodium bisulfite, 12 g, 1115.32 mmol) inorder to prevent the development of color in the product. The resultingmixture was then acidified to pH=2 using concentrated HCl. After stirredfor 1 h, the yellow ppt. that was formed in the solution mixture wascollected by filtration. The solid was washed with water and suspendedin water with SO₂ bubbling in the solution. After 30 minutes the solidagain was separated by filtration.

This wet solid was suspended in water, stirred, and dissolved by gradualaddition of solid Na₂CO₃. The solution was treated with a saturatedsolution of NaHSO₃ and filtered. The filtrate was acidified to pH=2using concentrated HCl. The solid that was formed in the solutionmixture was collected by filtration. The solid was washed with water,then resuspended in water, and again filtered. The solid was suspendedin EtOH, separated by filtration, and airdried to afford the desiredproduct as a brown solid. MS m/z: 316.2 (M+H). Calc'd. forC₁₀H₆INO₃−315.06.

6-iodoquinolin-3-ol. 3-hydroxy-6-iodoquinoline-4-carboxylic acid (22 g,70 mmol) was suspended in 1-nitrobenzene (143 ml, 1397 mmol) followed byadding Hunig's base (25 mL)-the suspension was completely dissolved. Theresulting mixture was heated to reflux (210° C.) under N₂. After 3 h,LC/MS showed no sign of starting material mass. The reaction mixture wascooled to rt; solvent was removed as much as possible in vacuo. Thecrude product was redissolved in DCM/MeOH and the solid was collected byfiltration. The solid was rinsed with hexane and either and dried asbrownish solid. The filtrate was removed excess solvent and purifiedusing SiO₂ chromatography (Teledyne Isco RediSep®, P/N 68-2203-058, 330g SiO₂, solvent system: hexanes:acetone=80%:20%, Flow=100 mL/min) toafford the desired product as brown solid. MS m/z: 272.3 (M+H). Calc'd.for C₉H₆INO−271.05.

tert-butyl 2-(3-hydroxyquinolin-6-yl)acetate. A stirred solution of6-iodoquinolin-3-ol (1.76 g, 6 mmol) in THF (10 mL) was treated with2-tert-butoxy-2-oxoethylzinc chloride (39 ml, 19 mmol) followed bytetrakis(triphenylphosphine)palladium(0) (0.8 g, 0.6 mmol). After theaddition, it was heated to reflux (75° C.) under N₂. After 3 h, TLC89368-3-1 showed no sign of starting material. Reaction was stop. Thereaction was cooled to rt. Solvent was removed. The residue was stirredin EtOAc/10% EDTA (50 mL/50 mL) solution mixture. After 1 h, the organiclayer was separated. The aqueous layer was extracted with more EtOAc(2×25 mL). The combined organic layers were washed with water, brine,dried over MgSO₄, and removed solvent. The crude product was purifiedusing SiO₂ chromatography (Teledyne Isco RediSep®, P/N 68-2203-026, 12 gSiO₂, hex:acetone=80%:20%, Flow=30 mL/min). to afford the desiredproduct as brownish liquid. MS m/z: 260.3 (M+H). Calc'd. forC₁₅H₁₇NO₃−259.2.

tert-butyl 2-(3-methoxyquinolin-6-yl)acetate. To a suspension oftert-butyl 2-(3-hydroxyquinolin-6-yl)acetate (0.1 g, 0.4 mmol) inbenzene (5 mL) was added methanol (0.05 ml, 1 mmol) andtributylphosphine (0.1 ml, 0.6 mmol). The resulting mixture was cooledto 0° C. followed by adding 1.1′-(azodicarbonyl)dipiperidine (0.1 g, 0.6mmol). After 10 min, ice bath was removed; the reaction mixture waswarmed up to rt. The reaction mixture was continued to stir for 20 h.TLC shadowed about 80% conversion. More MeOH (1 ml), tibutylphosphine(0.05 mL), and ADDP (50 mg) were added and allowed to stir for 3 h.Hexane was added to the reaction mixture and dihydro-ADDP separated outand was filtered off. The filtrate was concentrated. The crude productwas purified using SiO₂ chromatography (Teledyne Isco RediSep®, P/N68-2203-027, 40 g SiO₂) to afford the desired product as colorlessliquid. MS m/z: 274.3 (M+H). Calc'd. for C₁₆H₁₉NO₃−273.2.

6-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinolin-3-ol.To a 5 ml CEM microwave tube was added tert-butyl2-(3-methoxyquinolin-6-yl)acetate (0.3 g, 11 mmol),1-(6-phenylpyridazin-3-yl)hydrazine (0.3 g, 2 mmol), and HYDROCHLORICACID (0.3 ml, 11 mmol) as solvent. The vial was sealed and first heatedat 100° C. for 20 min then placed into CEM microwave for 20 min. at 180°C., with 100 Watts of power via Powermax. The reaction mixture wasadjusted the pH to 7 by adding 5 N NaOH. The ppt. was collected byfiltration. The ppt. was washed with water and dried. The solid waspurified using SiO₂ chromatography (Teledyne Isco RediSep®, P/N68-2203-027, 40 g SiO₂, DCM:MeOH=95%:5%, Flow=40 mL/min) to afford thedesired product as gray solid. MS m/z: 354.2 (M+H). Calc'd. forC₂₁H₁₅N₅O−353.37.

EXAMPLE 116

N,N-dimethyl-2-(6-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinolin-3-yloxy)ethanamine.6-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinolin-3-ol(0.05 g, 0.1 mmol) was dissolved in DMF (8 mL). SODIUM HYDRIDE (0.01 g,0.3 mmol) was added and allowed to stir for 1 h at rt.2-chloro-N,N-dimethylethanamine hydrochloride (0.06 g, 0.4 mmol), whichwas free-based using 5 N NaOH then extracted with ether, was added. Theresulting mixture was continued to stir for 20 h at rt. Solvent wasremoved in vacuo. The crude material was purified using SiO₂chromatography (Teledyne Isco RediSep®, P/N 68-2203-026, 12 g SiO₂,solvent system: DCM:MeOH(2M NH₃)=95%:5%, Flow=30 mL/min) to afford thetitle compound MS m/z: 425.3 (M+H). Calc'd. for C₂₅H₂₄N₆O−424.49.

tert-butyl 2-(3-methoxyquinolin-6-yl)proyanoate. To a flame-dry 100 ml3-neck round-bottomed flask was added lithium bis(trimethylsilyl)amide,1.0 m solution in tetrahydrofuran (5 ml, 5 mmol) and THF (20 mL). Themixture was cooled to −78° C. followed by adding tert-butyl2-(3-methoxyquinolin-6-yl)acetate (0.88 g, 3 mmol) in THF (10mL)dropwise via addition funnel. After stirring at −78° C. for 30 min,iodomethane (0.4 ml, 6 mmol) was added. The reaction mixture was stirredfor 30 min at −78° C. then allowed to warm to rt and stir for 1 h. Themixture was then quenched with sat. NH₄Cl (3 mL). Solvent was removed.The residue was partitioned between EtOAc/water. The organic layer waswashed with brine, dried over MgSO₄ and removed solvent. The crudematerial was purified using SiO₂ chromatography (Teledyne Isco RediSep®,P/N 68-2203-027, 40 g SiO₂, solvent system: hexane:acetone=90%:10%,Flow=30 mL/min) to afford a final product as yellowish liquid. MS m/z:288.4 (M+H). Calc'd. for C₁₇H₂₁NO₃−287.3.

EXAMPLE 117

3-methoxy-6-(1-(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinolineTo a 5 ml CEM microwave tube was added tert-butyl2-(3-methoxyquinolin-6-yl)propanoate (0.130 g, 0.45 mmol),1-(6-phenylpyridazin-3-yl)hydrazine (0.17 g, 0.90 mmol), HYDROCHLORICACID (0.11 ml, 1.4 mmol), and water (0.2 mL) as solvent. The vial wassealed and first heated at 90° C. for 30 min then placed into CEMmicrowave for 15 min. at 140° C., with 100 Watts of power via Powermax.The reaction mixture was adjusted the pH to 7 by adding 5 N NaOH and thesolid was collected by filtration. The brown ppt. was dissolved in DCM.The organic was washed with water, dried over MgSO₄, and removed solventin vacuo. The crude product was purified using SiO₂ chromatography(Teledyne Isco RediSep®, P/N 68-2203-027, 40 g SiO₂, DCM:MeOH=97%:3%,Flow=40 mL/min) to afford the desired product as light yellowish solid.MS m/z: 382.3 (M+H). Calc'd. for C₂₃H₁₉N₅O−381.43.

EXAMPLE 118

(S)-3-methoxy-6-(1-(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline.Chiral separation. MS m/z: 382.3 (M+H). Calc'd. for C₂₃H₁₉N₅O−381.43.

EXAMPLE 119

(R)-3-methoxy-6-(1-(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline.Chiral separation. MS m/z: 382.3 (M+H). Calc'd. for C₂₃H₁₉N₅O−381.43.

tert-butyl 2-(3-(2-methoxyethoxy)quinolin-6-yl)acetate. To a suspensionof tert-butyl 2-(3-hydroxyquinolin-6-yl)acetate (0.1 g, 0.4 mmol) inbenzene (5 mL) was added 2-methoxyethanol (0.09 ml, 1 mmol) andtri-n-butylphosphine (0.1 ml, 0.6 mmol). The resulting mixture wascooled to 0° C. followed by adding 1.1′-(azodicarbonyl)dipiperidine (0.1g; 0.6 mmol). After 10 min, ice bath was removed; the reaction mixturewas warmed up to rt. After 2 h, TLC showed there still existed 50%starting material. More methoxymethanol (2 eq, 0.06 mL) was added. Thereaction mixture was continued to stir for 20 h. Hexane was added to thereaction mixture and dihydro-ADDP separated out was filtered off. Thefiltrate was concentrated. The crude product was purified using SiO₂chromatography (Teledyne Isco RediSep®, P/N 68-2203-027, 40 g SiO₂,hexane:acetone=85%:15%, Flow=40 mL/min) to afford the desired product ascolorless liquid. MS m/z: 318.4 (M+H). Calc'd. for C₁₈H₂₃NO₄−317.38.

EXAMPLE 120

3-(2-methoxyethoxy)-6-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline.To a 5 ml CEM microwave tube was added tert-butyl2-(3-(2-methoxyethoxy)quinolin-6-yl)acetate (0.080 g, 0.25 mmol),1-(6-phenylpyridazin-3-yl)hydrazine (0.094 g, 0.50 mmol), HYDROCHLORICACID (0.063 ml, 0.76 mmol), and water (0.2 mL) as solvent. The vial wassealed and first heated at 90° C. for 30 min then placed into CEMmicrowave for 15 min. at 140° C., with 100 Watts of power via Powermax.The reaction mixture was adjusted the pH to 7 by adding 5 N NaOH and theprecipitate was collected via filtration. The brown ppt. was dissolvedin DCM. The organic was washed with water, dried over MgSO₄, and removedsolvent in vacuo. The crude product was purified using SiO₂chromatography (Teledyne Isco RediSep®, P/N 68-2203-026, 12 g SiO₂,DCM:EtOAc:MeOH=60%:37%:3%, Flow=30 mL/min) to afford the desired productas light yellowish solid. MS m/z: 412.3 (M+H). Calc'd. forC₂₄H₂₁N₅O₂−411.45.

methyl 2,2-difluoro-2-(Quinolin-6-yl)acetate. To a stirring solution ofmethyl 2-(quinolin-6-yl)acetate (450 mg, 2236 tμmol) in THF (2 mL) at−70° C. under nitrogen was added lithium bis(trimethylsilyl)amide, 1.0 msolution in tetrahydrofuran (5144 μl, 5144 μmol) and stirred for 10 min.To this solution was added n-fluorobis(phenylsulfonyl)amine (1481 mg,4696 μmol) in THF (5 mL) and slowly warmed to 0° C. over the course of 1h. Reaction stirred for an additional 1 h at 23° C., and resulting solid(sulfonamide) removed by filtration. The filtrate was concentrated to asolid under reduced pressure. The resulting solid was then partitionedbetween EtOAc (20 mL) and sat NH₄Cl (10 mL). The organic layer was driedover MgSO₄ then concentrated to a solid under reduced pressure and usedwithout further purification.

EXAMPLE 121

6-(difluoro(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline.A mixture of methyl 2,2-difluoro-2-(quinolin-6-yl)acetate (0.50 g, 2.1mmol), 1-(6-phenylpyridazin-3-yl)hydrazine (0.39 g, 2.1 mmol) andp-toluenesulfonic acid monohydrate (0.20 g, 1.1 mmol) in 5 mL of dioxanewas heated at 150° C. for 1 hour in a microwave tube in the microwave.The mixture was diluted with 70 mL of EtOAc and 40 mL of satd. NaHCO₃solution. The organic phase was separated and washed with 40 mL ofbrine, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by a silica gel column chromatography (EtOAc to 15% MeOH/EtOAc)to give yellow solid as desired product6-(difluoro(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline.MS (ESI pos. ion) m/z: 374.1 (M+H). Calc'd Exact Mass for C₂₁H₁₃F₂N₅:373.1.

tert-butyl 2-(4-aminoguinazolin-6-yl)acetate

To a solution of 6-bromoquinazolin-4-amine (0.400 g, 1.79 mmol),tris(dibenzylideneacetone)dipalladium (o) (0.163 g, 0.179 mmol) andQ-phos (0.20 g) in 10 mL of THF was added 2-tert-butoxy-2-oxoethylzincchloride 0.5 m in diethyl ether (10.7 ml, 5.36 mmol). The reaction washeated at 50° C. for 16 hours and was quenched with 50 mL of satd.NH₄Cl. The mixture was diluted with 60 mL of EtOAc. The organic phasewas separated, washed with brine, dried over Na₂SO₄ and concentrated invacuo to give red solid. The residue was purified by a silica gel columnchromatography (5% EtOAc/hex to EtOAC) to give red solid tert-butyl2-(4-aminoquinazolin-6-yl)acetate which was used without furtherpurification. MS (ESI pos. ion) m/z: 260.1 (M+H). Calc'd Exact Mass forC₁₄H₁₇N₃O₂: 259.1.

EXAMPLE 1226-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinazolin-4-amine

Prepared according to example 121 from tert-butyl2-(4-aminoquinazolin-6-yl)acetate. MS (ESI pos. ion) m/z: 354 (M+H).Calc'd Exact Mass for C₂₀H₁₅N₇: 353.

Mass General EX. Structure MW Found Method 123

383 384 A 124

304 305 A 125

303 304 B 126

318 319 C 127

431 432 C 128

388 388 A 129

483 483 A 130

440 441 A 131

440 441 A 132

458 459 A 133

426 427 A 134

402 403 B 135

475 475 A 136

378 379 B 137

461 461 A 138

436 436 A 139

462 462 A 140

454 455 A 141

425 426 A 142

465 466 A 143

424 424 A 144

414 415 B 145

384 385 B 146

413 414 B 147

360 361 B 148

359 360 B 149

328 329 B 150

354 355 B 151

384 385 B 152

384 385 B 153

442 443 D 154

385 386 A 155

452 453 A 156

486 486 A 157

451 452 A 158

398 398 B 159

382 383 D 160

399 400 B 161

383 384 D 162

412 412 B 163

397 398 B 164

397 398 B 165

472 473 B 166

397 398 D 167

397 398 D 168

398 399 B 169

358 359 D 170

409 410 D 171

419 420 A 172

437 438 A 173

461 461 A 174

401 402 A 175

436 436 A 176

403 404 A 177

419 420 A 178

436 436 A 179

452 452 A 180

425 425 A 181

411 411 A 182

401 401 C 183

338 337 C 184

389 390 A 185

451 452 A 186

414 415 A 187

414 415 D 188

402 403 A 189

427 428 A 190

411 412 A 191

431 432 A 192

531 531 A 193

507 507 A 194

415 416 A 195

415 416 A 196

411 412 A 197

415 416 A 198

486 486 A 199

491 491 A 200

414 415 A 201

477 477 A 202

452 453 A 203

453 454 A 204

402 403 A 205

384 385 A 206

389 390 A 207

413 414 A 208

372 373 A 209

384 385 A 210

462 462 A 211

408 409 A 212

401 402 A 213

401 402 A 214

373 374 A 215

403 404 A 216

451 452 A 217

419 420 A 218

467 468 A 219

419 420 A 220

437 438 A 221

403 404 A 222

404 405 A 223

418 418 A 224

452 452 A 225

452 452 A 226

404 405 A 227

530 530 D 228

436 436 A 229

557 557 A 230

453 454 A 231

452 453 A 232

441 442 A 233

387 388 A 234

387 388 D 235

401 402 D 236

440 441 A 237

458 459 A 238

445 446 A 239

428 429 A 240

416 417 A 241

417 418 A 242

458 459 A 243

431 432 D 244

427 428 D 245

418 419 A 246

436 437 A 247

418 419 D 248

436 437 D 249

396 397 A 250

400 401 A 251

450 451 A 252

400 401 A 253

466 467 A 254

418 419 A 255

466 467 A 256

400 401 A 257

460 460 A 258

425 426 A 259

474 474 A 260

407 408 A 261

384 385 A 262

384 385 A 263

388 389 A 264

383 384 A 265

418 419 A 266

418 419 A 267

436 437 A 268

512 512 A 269

468 469 A 270

423 423 A 271

389 390 A 272

414 415 A 273

414 415 A 274

426 427 A 275

430 431 A 276

435 435 A 277

417 417 A 278

413 414 A 279

403 404 A 280

403 404 A 281

384 385 A 282

383 384 A 283

371 372 A 284

382 383 A 285

388 389 A 286

457 458 A 287

402 403 A 288

389 390 A 289

488 488 A 290

389 390 A 291

403 404 A 292

432 433 A 293

403 404 A 294

437 438 A 295

421 422 D 296

421 422 D 297

387 388 A 298

454 455 D 299

419 420 A 300

400 401 A 301

475 476 A 302

420 421 A 303

418 419 A 304

436 437 A 305

432 433 A 306

339 339.1, 341.3 B 307

336 337 A 308

341 342 A 309

440 441 D 310

437 438 D 311

404 405 D 312

431 432 D 313

427 428 D 314

340 341 E 315

337 338 E 316

304 305 A 317

316 317 A 318

302 303 B 319

303 304 A 320

320 321 A 321

291 292 A 322

315 316 A 323

382 383 B 324

395 396 E 325

301 459 E 326

330 331 A 327

378 379 A 328

337 337 A 329

347 348 A 330

392 393 A 331

317 318 A 332

343 344 A 333

338 339 A 334

353 354 A 335

355 356 A 336

357 358 A 337

391 393 A 338

373 374 A 339

355 356 A 340

373 375 A 341

341 343 A 342

353 354 E 343

342 343 E 344

390 391 D 345

420 421 D 346

418 419 D 347

432 433 D 348

423 424 D 349

449 450 D 350

455 456 D 351

402 403 A 352

387 388 A 353

358 359 D 354

407 408 D 355

374 375 D 356

433 434 D 357

475 476 D 358

441 442 A 359

392 393 D 360

404 405 D 361

462 463 D 362

476 477 D 363

474 475 D 364

440 441 D 365

448 449 D 366

500 501 D 367

520 521 D 368

505 506 D 369

502 503 D 370

463 464 D 371

487 488 D 372

472 473 D 373

500 501 D 374

455 456 D 375

499 500 D 376

484 485 D 377

485 486 D 378

485 485 D 379

538 539 D 380

520 521 D 381

505 506 D 382

500 501 D 383

437 438 D 384

485 486 D 385

517 518 D 386

398 399 D 387

505 506 D 388

522 523 D 389

443 444 D 390

413 414 D 391

414 415 D 392

488 489 D 393

351 352 D 394

388 388 D 395

350 351 D 396

364 365 D 397

489 490 D 398

440 441 D 399

420 421 D 400

425 426 D 401

396 397 D 402

363 364 D

EXAMPLE 403(R)-N-((6-(3,5-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-(pyrrolidin-2-ylmethoxy)-1,5-naphthyridin-4-amine

a) (R)-tert-butyl2-((8-((6-(3,5-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylamino)-1,5-naphthyridin-3-yloxy)methyl)pyrrolidine-1-carboxylatewas prepared according to method D.

b)(R)-N-((6-(3,5-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-(pyrrolidin-2-ylmethoxy)-1,5-naphthyridin-4-amine.The title compound was prepared from (R)-tert-butyl2-((8-((6-(3,5-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylamino)-1,5-naphthyridin-3-yloxy)methyl)pyrrolidine-1-carboxylatefollowing the procedure used to make7-methoxy-4-((6-(6-(piperazin-1-yl)pyridin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)quinoline.m/z: 489 (M+H). Calc'd. for C₂₅H₂₂F₂N₈O−488.

EXAMPLE 404(S)-N-((6-(3,5-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-(pyrrolidin-2-ylmethoxy)-1,5-naphthyridin-4-amine

The title compound was prepared in the same manner as(R)-N-((6-(3,5-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-(pyrrolidin-2-ylmethoxy)-1,5-naphthyridin-4-amine.m/z: 489 (M+H). Calc'd. for C₂₅H₂₂F₂N₈O−488.

EXAMPLE 4057-methoxy-N-((6-(2-morpholinothiazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine 1)4-(4-bromothiazol-2-yl)morpholine

To a microwave vial was added N,N-diisopropylethylamine (0.86 ml, 4.9mmol), 2,4-dibromothiazole (1.00 g, 4.1 mmol), and morpholine (0.43 ml,4.9 mmol) in EtOH (4 mL). The mixture was heated under microwaveirradiation at 140° C. for 35 minutes. The reaction mixture wasconcentrated in vacuo. The crude material was dissolved in minimalDCM/MeOH and purified via MPLC (eluting with 0-30% EtOAc in hexnaes) toyield 4-(4-bromothiazol-2-yl)morpholine (0.700 g, 68% yield) as a whitesolid.

2) 4-(4-(trimethylstannyl)thiazol-2-yl)morpholine

Prepared in a method similar to 3-methyl-5-trimethylstannyl)isothiazole.

3)Bis-tert-butyl(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate

Di-tert-butyl dicarbonate (24.42 g, 111.9 mmol) was added to a stirredsuspension of tert-butyl(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (10.58 g,37.3 mmol) in acetonitrile (200 mL) at 0° C. followed by4-dimethylaminopyridine (4.556 g, 37.3 mmol). Stirring was continued at0° C. for ˜10 min then the cooling bath was removed and stirring wascontinued at room temperature overnight. The reaction mixture wasconcentrated in vacuo, diluted with EtOAc and washed with water. Theorganic layer was dried over MgSO₄, filtered and concentrated in vacuo.Purification via MPLC (EtOAc/MeOH: 100/0 to 90/10) afforded the titlecompound (14.3 g, 37.3 mmol, 100% yield).

4)(6-(2-morpholinothiazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyldi-tert-butyl carbamate

To a pressure vessel purged with argon was added palladium (II) acetate(0.0029 g, 0.013 mmol), Xantphos (0.015 g, 0.026 mmol) andbis-tert-butyl(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate(0.100 g, 0.26 mmol) in 1,4-dioxane (0.17 M, 1.5 mL).4-(4-(trimethylstannyl)thiazol-2-yl)morpholine (0.13 g, 0.39 mmol) anddegassed water (0.0094 ml, 0.52 mmol) were added, once more purging theflask with argon. The reaction mixture was stirred at 100° C. for 4 huntil complete consumption of the starting material. The reactionmixture was concentrated in vacuo. The crude material was dissolved inminimal EtOAc and purified via MPLC (eluting with 100% EtOAc).(6-(2-morpholinothiazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyldi-tert-butyl carbamate (0.086 g, 64% yield) was obtained as a solid.The material was carried forward without further purification.

5)7-methoxy-N-((6-(2-morpholinothiazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine

To a microwave vial was added(6-(2-morpholinothiazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyldi-tert-butyl carbamate (0.086 g, 0.17 mmol) and8-chloro-3-methoxy-1,5-naphthyridine (0.036 g, 0.18 mmol) in 2-butanol(1.0 mL). The vial was sealed and heated under microwave irradiation at120° C. for 6 h. The reaction was concentrated in vacuo. The crudematerial was dissolved in 2M ammonia in methanol and purified via MPLC(eluting with 0-10% 1% NH₄OH/in DCM).7-methoxy-N-((6-(2-morpholinothiazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine(0.031 g, 39% yield) was obtained as a yellow solid. m/z: 476.0 (M+H).Calc'd. for C₂₂H₂₁N₉O₂S−475.53.

The following example compounds 406 and 407 were prepared using themethod to make7-methoxy-N-((6-(2-morpholinothiazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine:

Mass Ex Structure MW Found 406

390 391 407

390 391

The following example compounds 408-428 were prepared using steps 1 and2 of Method A. Where applicable, enantiomer was obtained via SFC:

Mass Ex Structure MW Found 408

389 390 409

404 405 410

389 389 411

403 404 412

404 405 413

407 408 414

373 374 415

373 374 416

372 373 417

372 373 418

443 444 419

403 404 420

407 408 421

419 420 422

419 420 423

434 435 424

434 435 425

402 403 426

402 403 427

422 423 428

422 423

1-(3-fluoro-5-(3-methylisothiazol-5-yl)pyridin-2-yl)hydrazine

5-chloro-2,3-difluoropyridine (0.069 ml, 0.67 mmol), X-Phos (0.045 g,0.094 mmol) and palladium (II) acetate (0.011 g, 0.047 mmol) werecombined in 1,4-dioxane (0.2 M, 3.4 mL). To the reaction vessel wasadded 3-methyl-5-(trimethylstannyl)isothiazole (0.53 g, 2.0 mmol) and,after purging with argon, the reaction was stirred at 100° C. for 2 hand then concentrated in vacuo. The crude material was dissolved inminimal DCM and purified via MPLC (eluting first with 100% EtOAcfollowed by 20% EtOAc in hexanes-isocratic) to yield2,3-difluoro-5-(3-methylisothiazol-5-yl)pyridine (0.139 g, 98% yield) asa yellow solid. 2,3-difluoro-5-(3-methylisothiazol-5-yl)pyridine wasconverted to the title compound using a procedure similar to1-(4-methyl-6-phenylpyridazin-3-yl)hydrazine.

1-(5-(3,5-difluorophenyl)-3-fluoropyridin-2-yl)hydrazine

A mixture of palladium (II) acetate (0.0375 g, 0.167 mmol), potassiumphosphate (2.13 g, 10.0 mmol), 3,5-difluorophenylboronic acid (1.58 g,10.0 mmol), X-Phos (0.159 g, 0.334 mmol) and5-chloro-2,3-difluoropyridine (0.347 ml, 3.34 mmol) was diluted with1,4-dioxane (0.1M, 33.4 mL) and water (0.3M, 11.0 mL) and was heatedunder nitrogen at 100° C. for 45 minutes. The reaction was concentratedin vacuo. The concentrated material was triturated with water, filteredand rinsed with MeCN. The crude solid was taken up in dichloromethaneand filtered over a plug of Celite to eliminate residual palladium. Thematerial was dissolved in minimal DCM, and purified via MPLC (elutingwith 0-10% EtOAc in hexanes) to yield5-(3,5-difluorophenyl)-2,3-difluoropyridine. The material was convertedto the hydrazine in a method similar to that in the synthesis of(S)-6-(1-(8-fluoro-6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)quinoline.

The following compounds were prepared using a similar method as1-(5-(3,5-difluorophenyl)-3-fluoropyridin-2-yl)hydrazine:

-   1) 1-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)hydrazin

The following compounds were prepared using a similar method (usingeither the trimethyl- or tributyl-stannnane) as1-(3-fluoro-5-(3-methylisothiazol-5-yl)pyridin-2-yl)hydrazine:

-   1-(3-fluoro-5-(3-methylisoxazol-5-yl)pyridin-2-yl)hydrazine; and-   1-(3-fluoro-5-(3-trifluoromethylisoxazol-5-yl)pyridin-2-yl)hydrazine.

2-(3-methoxyquinolin-6-yl)propanoic acid hydrochloride

Tert-butyl 2-(3-methoxyquinolin-6-yl)propanoate (0.865 g, 3.01 mmol) wasdissolved in EtOAc (0.2M, 15 mL), and HCl (g) (0.0915 ml, 3.01 mmol) wasbubbled through the solution for approximately 5 minutes. The reactionvessel was sealed and the reaction was stirred at room temperature for1.5 h until completion. The reaction mixture was concentrated in vacuoto yield 2-(3-methoxyquinolin-6-yl)propanoic acid hydrochloride (0.805g, 99.9% yield) as an orange solid.

2-fluoro-2-(quinolin-6-yl)propanoic acid

To a solution of methyl 2-(quinolin-6-yl)propanoate (0.868 g, 4.03 mmol)in THF (1.1M, 3.7 mL) at −78° C. was added LiHMDS (1M in THF) (5.24 ml,5.24 mmol). The reaction was stirred at −78° C. for ˜15 minutes, then toit was added a solution of N-fluorobenzenesulfonimide (1.40 g, 4.44mmol) in THF (1.0M, 4.5 mL). The reaction was allowed to warm to −10° C.over 2 h. The reaction was filtered through a plug of Celite, washedwith EtOAc and the filtrate was then concentrated in vacuo. Theconcentrated material was rediluted with EtOAc and washed with saturatedNH₄Cl solution. The aqueous layer was then extracted with EtOAc, and theorganic layers were dried over MgSO₄, filtered and concentrated invacuo. The crude material was dissolved in minimal DCM and purified viaMPLC (eluting with isocratic 40% EtOAc:Hexanes to yield methyl2-fluoro-2-(quinolin-6-yl)propanoate (0.709 g, 75.4% yield) as a yellowoil. To synthesize the corresponding acid, methyl2-fluoro-2-(quinolin-6-yl)propanoate was saponified in a method similarto that of 2-(quinolin-6-yl)propanoic acid.

2-(3-methoxyquinolin-6-yl)acetic acid hydrochloride

tert-Butyl 2-(3-methoxyquinolin-6-yl)acetate was saponified in a methodsimilar to 2-(3-methoxyquinolin-6-yl)propanoic acid hydrochloride.

(6-(2-methoxythiazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanamine

The di-tert-butyl carbonate precursor((6-(2-methoxy-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyldi-tert-butyl carbamate) was synthesized in a method similar to(6-(2-morpholinothiazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyldi-tert-butyl carbamate, using 2-methoxy-4-(tributylstannyl)thiazole asthe organostannane, followed by TFA deprotection similar to the methoddescribed for(6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanamine.

EXAMPLE 4294-((8-fluoro-6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-(2-methoxyethoxy)quinoline 1)2-(7-hydroxyquinolin-4-yloxy)acetic acid hydrobromide

To a pressure vial was added 2-(7-methoxyquinolin-4-yloxy)acetic acid(1.00 g, 4.29 mmol) in DCE (0.6 M, 7 mL). The vial was cooled in an icebath and to the solution was added BBr₃ (1.62 ml, 17.2 mmol). Thereaction was allowed to warm to room temperature and stirred overnight.While some starting material remained, the reaction was stopped anddiluted with DCM (keep in hood due to fuming). The solids were filteredand dried over high vacuum to yield a light brown crude solid (˜1.8 g).The material was used without further purification.

2)4-((8-fluoro-6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)quinolin-7-ol

The material was prepared using general method A (with2-(7-hydroxyquinolin-4-yloxy)acetic acid hydrobromide and1-(3-fluoro-5-(3-methylisoxazol-5-yl)pyridin-2-yl)hydrazine

3)4-((8-fluoro-6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-(2-methoxyethoxy)quinoline

4-((8-fluoro-6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)quinolin-7-ol(0.110 g, 0.28 mmol), PPh₃ (polymer supported: 2.3 mmol/g) (1.2 g, 2.8mmol) and 2-methoxyethanol (0.11 ml, 1.3 mmol) were combined in DCM (11ml, 0.28 mmol). The mixture was cooled to 0° C., and DEAD (0.089 ml,0.56 mmol) was added dropwise. The reaction was removed from the icebath, and stirred at RT for 1 h. The material was diluted with DCM, andthe PS-PPh₃ was filtered off and washed thoroughly with DCM. Thefiltrate was concentrated in vacuo. The crude material was dissolved inminimal DCM and purified via MPLC (eluting with 0-100% 90:10:1DCM:MeOH:NH₄OH in DCM) to yield4-((8-fluoro-6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-(2-methoxyethoxy)quinoline(0.070 g, 55% yield) as a white solid. MS (ESI pos. ion) m/z: 450.0(M+H). Calc'd Exact Mass for C₂₃H₂₀FN₅O₄: 449.44

tert-Butyl(6-(3-hydroxy-4-methylpent-1-ynyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate

In a 15-mL sealed tube flushed with nitrogen, tert-butyl(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (2.00 g,7.0 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (0.58 g, 0.70 mmol), and copper (I)iodide (0.34 g, 1.8 mmol) were diluted in MeCN (70 mL). To the reactionmixture was first added 4-methylpent-1-yn-3-ol (3.7 ml, 35 mmol),followed by triethylamine (25 ml, 176 mmol). The reaction was thenheated at 50° C. for 7.5 h. The crude material was dissolved in minimalDCM and purified via MPLC (twice)(eluting with 0-10% MeOH/NH₄OH:DCM) toyield tert-butyl(6-(3-hydroxy-4-methylpent-1-ynyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate(1.823 g, 75% yield) as a light brown solid.

tert-Butyl(6-(4-methyl-3-oxopent-1-ynyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate

tert-Butyl(6-(3-hydroxy-4-methylpent-1-ynyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate(1.82 g, 5.27 mmol) and manganese dioxide (activated) (9.16 g, 105 mmol)were dissolved in DCM (263 mL) and stirred at room temperature over twodays. Additional manganese dioxide (activated) (4.58 g, 52.7 mmol) wasadded and stirring continued overnight. The reaction mixture wasfiltered over a plug of Celite and washed with DCM to yield tert-butyl(6-(4-methyl-3-oxopent-1-ynyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate(0.917 g, 50.7% yield) after concentration in vacuo.

tert-Butyl(6-(3-isopropylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate

An aqueous mixture of tert-butyl(6-(4-methyl-3-oxopent-1-ynyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate(0.800 g, 2.33 mmol) and hydroxylamine-O-sulfonic acid (0.263 g, 2.33mol) in water (8.0 mL) and 1,4-dioxane (8.0 mL) was stirred at 0° C.until complete consumption of the organic starting material wasobserved. The mixture was then carefully treated with solid sodiumbicarbonate (0.196 g, 2.33 mmol), followed by treatment with 1.4 Maqueous sodium hydrosulfide (1.83 ml, 2.56 mmol). The reaction wasstirred at room temperature overnight. The reaction mixture was dilutedwith water (20 mL) and extracted with DCM (40 mL), dried over sodiumsulfate, filtered and concentrated in vacuo. The concentrated crudematerial was dissolved in minimal DCM and was purified via MPLC (elutingwith 0-10% MeOH/NH₄OH in DCM) to yield tert-butyl(6-(3-isopropylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate(0.196 g, 22.5% yield) with 82% purity. MS (ESI pos. ion) m/z: 433.0(M+H). Calc'd Exact Mass for C₂₁H₂₀N₈OS: 432.51.

EXAMPLE 4301-(6-Phenylimidazo[1,2-b]pyridazin-3-yl)-1-(quinolin-6-yl)ethanol a)N-methoxy-N-methylquinoline-6-carboxamide

A 250 mL RB flask was charged with quinoline-6-carboxylic acid (5.00 g,28.9 mmol), DCM (100 ml, 1554 mmol), oxalyl chloride (3.79 ml, 43.3mmol), and a few drops of DMF and stirred at RT for 2 hours, thenconcentrated. The residue was taken up in DCM (100 ml, 1554 mmol),cooled to 0° C., then Hunig's Base (17.7 ml, 101 mmol) andN-methoxymethanamine hydrochloride (2.96 g, 30.3 mmol) were addedslowly. The mixture was stirred at room temperature for 16 hours(91463-3-1). The mixture was diluted with DCM (200 mL), then washed withwater (250 mL), sat. NaHCO₃ (250 mL), and brine (250 mL). The organiclayer was dried with MgSO₄, filtered, and concentrated to give a brownoil, which was purified by MPLC eluting with 2-6% MeOH/DCM to giveN-methoxy-N-methylquinoline-6-carboxamide (5.943 g, 95.2% yield) as abrown oil.

b) 1-(quinolin-6-yl)ethanone

A 250 mL RB flask was charged withN-methoxy-N-methylquinoline-6-carboxamide (5.943 g, 27.5 mmol) and THF(100 ml, 1220 mmol), then cooled to 0 C. Methylmagnesium bromide (18.3ml, 55.0 mmol) was added dropwise and the mixture was allowed to warm toroom temperature and stirred for 3 hours. The reaction was not quitecomplete, so additional MeMgBr (3 mL) was added and the mixture wasstirred overnight. The mixture was then neutralized using 2N HCl and theaqueous layer was extracted with DCM (200 mL×2) and EtOAc (200 mL×2).The organic layer was dried with MgSO₄, filtered, and concentrated togive a yellow oil. The aqueous layer contained some product, so thelayer was concentrated and then filtered thru a reverse phase C₁₈column, first eluting with water than with MeOH. The MeOH layer wasconcentrated to give a yellow oil which was combined with the yellow oilfrom the organic layer. The combined portions were purified by MPLCeluting with a gradient of 2-6% MeOH/DCM. 1-(quinolin-6-yl)ethanone(4.074 g, 86.6% yield) was isolated as a yellow oil which solidifiedupon standing.

c) 2-bromo-1-(quinolin-6-yl)ethanone hydrobromide

A 250 mL RB flask was charged with 1-(quinolin-6-yl)ethanone (3.82 g,22.3 mmol) and 30% HBr/AcOH (45.0 ml). Bromine (1.14 ml, 22.1 mmol) wasadded slowly. This was stirred at room temperature for 4 hours, at whichpoint full conversion to product (with a small amount of dibrominatedside product) was observed. The reaction mixture was filtered and thesolid was washed with Et₂O to give 2-bromo-1-(quinolin-6-yl)ethanonehydrobromide (5.6359 g, 76.3% yield).

The compound was used in the next step without further purification.

d) (E)-N′-(6-chloropyridazin-3-yl)-N,N-dimethylformamidine

A 500 mL RB flask was charged with 6-chloropyridazin-3-amine (10.0 g,77.2 mmol) and dimethoxy-N,N-dimethylmethanamine (206 ml, 1544 mmol),equipped with a reflux condenser, then heated to 110° C. for 3 hoursthen left at room temperature for 16 hours. The precipitate wascollected by filtration. The mother liquor was concentrated down to givean yellow solid, which was triturated with EtOAc and collected. Thesolids were combined to give(E)-N′-(6-chloropyridazin-3-yl)-N,N-dimethylformamidine (11.81 g, 82.9%yield) as a white solid

e) (6-Chloroimidazo[1,2-b]pyridazin-3-yl)(quinolin-6-yl)methanone

A 100 mL RB flask was charged with 2-bromo-1-(quinolin-6-yl)ethanone(0.7011 g, 2.80 mmol),(E)-N′-(6-chloropyridazin-3-yl)-N,N-dimethylformamidine (0.518 g, 2.80mmol), and DMF (10.0 ml, 129 mmol), equipped with a reflux condenser,then heated at 105° C. for 3 hours. The reaction mixture wasconcentrated, then triturated with MeOH to yield(6-chloroimidazo[1,2-b]pyridazin-3-yl)(quinolin-6-yl)methanone (0.530 g,1.72 mmol, 61%) as a brown solid.

f) (6-Phenylimidazo[1,2-b]pyridazin-3-yl)(quinolin-6-yl)methanone

A 48 mL sealed tube was charged with(6-chloroimidazo[1,2-b]pyridazin-3-yl)(quinolin-6-yl)methanone (0.530 g,1.72 mmol), phenylboronic acid (0.314 g, 2.58 mmol), cesium carbonate(1.68 g, 5.15 mmol), PdCl₂(dppt)-CH₂Cl₂ adduct (0.0701 g, 0.0858 mmol),1,4-dioxane (6.31 ml, 73.8 mmol), and water (1.11 ml, 61.8 mmol),flushed with argon, sealed, then placed in an 80° C. oil bath for 8hours. The mixture was concentrated then triturated with water, followedby MeOH/DCM to give(6-phenylimidazo[1,2-b]pyridazin-3-yl)(quinolin-6-yl)methanone as areddish brown solid.

g) 1-(6-Phenylimidazo[1,2-b]pyridazin-3-yl)-1-(quinolin-6-yl)ethanol

A 25 mL RB flask was charged with(6-phenylimidazo[1,2-b]pyridazin-3-yl)(quinolin-6-yl)methanone (0.200 g,0.57 mmol) and THF (2.00 ml, 24 mmol), then cooled to 0° C.methylmagnesium bromide (0.76 ml, 2.2 mmol) was added dropwise and themixture was stirred at room temperature for 5 hours. This was dilutedwith 2 N HCl (1 mL) and water (25 mL), then extracted with DCM (25 mL×2)and EtOAc (25 mL). The combined organics were washed with brine anddried with MgSO₄, filtered, and concentrated. The resulting oil waspurified by MPLC using a 40 g RediSep column, eluting with 2-6% MeOH/DCMover 40 minutes.1-(6-phenylimidazo[1,2-b]pyridazin-3-yl)-1-(quinolin-6-yl)ethanol (0.082g, 39% yield) was isolated as a tan solid. MS (ESI pos. ion) m/z: 367(MH+). Calc'd exact mass for C₂₃H₁₈N₄O: 366.

EXAMPLE 431 6-((6-Phenylimidazo[1,2-b]pyridazin-3-yl)methyl)quinoline

A 10-20 mL microwave vial was charged with hydrazine hydrate (0.0312 ml,0.642 mmol),(6-phenylimidazo[1,2-b]pyridazin-3-yl)(quinolin-6-yl)methanone (0.150 g,0.428 mmol), KOH (0.0961 g, 1.71 mmol), and diethylene glycol (4.09 ml,42.8 mmol), sealed, then placed in a Personal Chemistry microwave at130° C. for 20 minutes after a 5 minute pre-stir. The mixture wasdiluted with water (75 mL), then extracted with DCM (2×75 mL). Thecombined organics were washed with brine (75 mL), then dried with MgSO₄,filtered, and concentrated to give a brown solid, then purified by prepHPLC to give the product as the formic acid salt. MS (ESI pos. ion) m/z:337 (MH+). Calc'd exact mass for C₂₂H₁₆N₄: 336.

EXAMPLE 4326-((6-(3-Methylisoxazol-5-yl)imidazo[1,2-b]pyridazin-3-yl)methyl)quinoline

A 16 mm test tube was charged with hydrazine hydrate (0.0273 ml, 0.563mmol),(6-(3-methylisoxazol-5-yl)imidazo[1,2-b]pyridazin-3-yl)(quinolin-6-yl)methanone(prepared using a similar procedure as(6-phenylimidazo[1,2-b]pyridazin-3-yl)(quinolin-6-yl)methanone) (0.100g, 0.281 mmol), sodium tert-butoxide (0.0406 g, 0.422 mmol), and1-butanol (0.670 ml, 7.32 mmol), sealed, then heated to 150° C. for 2hours (96979-1-1). The mixture was diluted with water, neutralized with2 N HCl, then extracted with DCM (3×30 mL). The combined organics weredried with MgSO₄, filtered, then concentrated.6-((6-(3-methylisoxazol-5-yl)imidazo[1,2-b]pyridazin-3-yl)methyl)quinolinewas purified by prep HPLC and isolated as the TFA salt. MS (ESI pos.ion) m/z: 341 (MH+). Calc'd exact mass for C₂₀H₁₅N₅O: 341.

EXAMPLE 4336-(difluoro(6-(3-methylisoxazol-5-yl)imidazo[112-b]pyridazin-3-yl)methyl)quinoline

A 25 mm test tube was charged with2,2-difluoro-1,3-dimethylimidazolidine (DFI) (0.24 g, 1.8 mmol),(6-(3-methylisoxazol-5-yl)imidazo[1,2-b]pyridazin-3-yl)(quinolin-6-yl)methanone(0.125 g, 0.35 mmol), and MeCN (2.00 ml, 38 mmol), sealed, then heatedat 84° C. for 36 hours, adding additional2,2-difluoro-1,3-dimethylimidazolidine (DFI) (0.24 g, 1.8 mmol) after 16hours. The mixture was diluted with water (50 mL), then extracted withDCM (2×40 mL). The combined organics were washed with brine (40 mL),dried with MgSO₄, filtered, then concentrated to give a brown residue.This was purified by MPLC using a 40 g RediSep column, eluting with20-50% (90:10:1 DCM:MeOH:NH₄OH mixture) in EtOAc over 40 minutes. Thepurest fractions were collected—these still contained DFI, so theresidue was triturated with EtOAc and decanted.6-(difluoro(6-(3-methylisoxazol-5-yl)imidazo[1,2-b]pyridazin-3-yl)methyl)quinolinewas isolated as a light yellow solid. MS (ESI pos. ion) m/z: 378 (MH+).Calc'd exact mass for C₂₀H₁₃F₂N₅O: 377.

EXAMPLE 4347-(difluoromethoxy)-4-((6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)quinoline

1)4-((6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)quinolin-7-olhydrobromide

A 150 mL tube was charged with7-methoxy-4-((6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)quinoline(1.44 g, 3.72 mmol) and HBr (30.3 ml, 558 mmol), sealed, then placed ina 120° C. for 5 hours. The reaction mixture was slowly neutralized with6N NaOH until a precipitate crashed out of solution (pH ˜5)—the solidwas collected to give4-((6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)quinolin-7-olhydrobromide.

2)7-(difluoromethoxy)-4-((6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)quinoline

A 48 mL tube was charged with sodium 2-chloro-2,2-difluoroacetate (0.15g, 1.0 mmol),4-((6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)quinolin-7-olhydrobromide (0.200 g, 0.44 mmol), cesium carbonate (0.43 g, 1.3 mmol),and DMF (1.7 ml, 22 mmol), flushed with argon, sealed, then placed in a100° C. oil bath for 5 hours. The reaction mixture was concentrated,then diluted with DCM and chloroform. This was washed with water, sat.NaHCO₃, and brine, then dried with MgSO₄, filtered, and concentrated togive a brown oil. This was purified by HPLC to give7-(difluoromethoxy)-4-((6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)quinoline(0.025 g, 13% yield) as the formic acid salt. MS (ESI pos. ion) m/z: 424(MH+). Calc'd exact mass for C₂₁H₁₅F₂N₅O₃: 423.

EXAMPLE 435N-((6-(1H-indazol-6-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine

a)6-(3-((7-Methoxy-1,5-naphthyridin-4-ylamino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-indazole-1-carboxylate.A tube was charged withN-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine(0.250 g, 0.732 mmol), tert-butyl6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-1-carboxylate(0.378 g, 1.10 mmol), PdCl2(dppf)-CH2Cl2Adduct (0.0597 g, 0.0732 mmol),potassium carbonate (0.303 g, 2.19 mmol), DMF (5.01 ml, 64.4 mmol), andwater (1.16 ml, 64.4 mmol), flushed with argon, sealed, then placed in a60° C. oil bath for 6 hours. The reaction mixture was concentrated, thentriturated with water to give a black solid. The material was useddirectly in the next step.

b)N-((6-(1H-indazol-6-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine.The title compound was prepared in the same manner as7-methoxy-4-((6-(6-(piperazin-1-yl)pyridin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)quinolineMS (ESI pos. ion) m/z: 424 (MH+). Calc'd exact mass for C₂₂H₁₇N₉O: 423.

4-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazole

A 250 mL RB flask was charged with 4-bromo-1H-pyrazole (2.00 g, 13.6mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.35 ml, 17.0mmol), cesium carbonate (8.87 g, 27.2 mmol), and 1,4-dioxane (40.0 ml,468 mmol), capped, and stirred at room temperature for 20 hours. Thereaction mixture was filtered and the solid washed with dioxane; thefiltrate was then concentrated to give4-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazole (2.402 g, 77.1% yield) as acrude oil.

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole

The title compound was prepared in the same manner as1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolestarting with 4-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazole.

EXAMPLE 4367-methoxy-N-((6-(3-methylisothiazol-5-yl)imidazo[1,2-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine

The title compound was prepared in the same manner as7-Methoxy-N-((6-(3,4,5-trifluorophenyl)imidazo[1,2-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine.MS (ESI pos. ion) m/z: 404 (MH+). Calc'd exact mass for C₂₀H₁₇N₇OS: 403.

(5-(3-(aminomethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)isothiazol-3-yl)methanol

1) 5-bromo-3-(dibromomethyl)isothiazole. 5-Bromo-3-methylisothiazole(2.15 g, 12 mmol) was dissolved in dichloroethane (20 mL) then addedN-bromosuccinimide (4.5 g, 25 mmol) and AIBN (0.50 g, 3.0 mmol). Thereaction mixture was heated at 100° C. for 4 hours. Additional AIBN(0.50 g, 3.0 mmol) and bromine (0.062 ml, 1.2 mmol) were added to themixture and continued heating at 100° C. for 4 hours. N-bromosuccinimide(4.5 g, 25 mmol) and AIBN (0.50 g, 3.0 mmol) were added then continuedheating at 100° C. for 4 hours. Again, N-bromosuccinimide (4.5 g, 25mmol) and AIBN (0.30 g, 1.8 mmol) were added and the mixture was heatedat 100° C. for 4 hours. The reaction mixture was diluted with ethylacetate and washed with water, saturated sodium bicarbonate and brine.The organic layer was dried over sodium sulfate and concentrated undervacuum. The sample was purified by flash chromatography eluting with0-10% ethyl acetate/hexane to afford5-bromo-3-(dibromomethyl)isothiazole (2.07 g, 51% yield) as a colorlessliquid.

2) 5-bromoisothiazole-3-carbaldehyde.5-Bromo-3-(dibromomethyl)isothiazole (1.00 g, 3.0 mmol) was dissolved inDME (10 mL) then added a solution of silver nitrate (0.56 g, 3.3 mmol)in water (1.6 mL). A white precipitate formed. The reaction mixture washeated at 100° C. for 1.5 hours. Additional silver nitrate (0.56 g, 3.3mmol) in water (1.6 mL) was added and heating was continued at 100° C.for 2.5 hours. The reaction mixture was filtered through a pad of Celitewashing with THF then ethyl acetate. The filtrate was concentrated undervacuum and the remaining oil was diluted with ethyl acetate. The organiclayer was washed with water then dried over sodium sulfate andconcentrated under vacuum to afford 5-bromoisothiazole-3-carbaldehyde(0.536 g, 94% yield) as alight yellow oil.

3)(5-bromoisothiazol-3-yl)methanol. 5-Bromoisothiazole-3-carbaldehyde(0.533 g, 2.8 mmol) was dissolved in ethanol (40 mL) then added sodiumborohydride (0.11 g, 2.8 mmol). The reaction mixture was stirred at roomtemperature for 3 hours. Added more sodium borohydride (0.026 g, 0.69mmol) and continued stirring at room temperature for 4.5 hours.Additional sodium borohydride (0.11 g, 2.8 mmol) was added once againand stirring was continued at room temperature overnight. The reactionwas quenched with saturated aqueous ammonium chloride then concentratedunder vacuum. The remaining aqueous layer was diluted with water thenextracted with ethyl acetate (2×). The organic layer was dried oversodium sulfate and concentrated under vacuum to afford(5-bromoisothiazol-3-yl)methanol (0.430 g, 80% yield) as an orange oil.MS (ESI pos. ion) m/z: 194.0 and 196.0 (MH⁺).

4) 5-bromo-3-((tert-butyldimethylsilyl oxy)methyl)isothiazole.(5-Bromoisothiazol-3-yl)methanol (0.380 g, 1.96 mmol) was dissolved inDMF (4 mL) then added tert-butyldimthylsilyl chloride (0.443 g, 2.94mmol) and imidazole (0.400 g, 5.87 mmol). The reaction mixture wasstirred at room temperature overnight. The reaction mixture was combinedwith previous reactions and concentrated under vacuum. The sample waspurified by flash chromatography eluting with 0-15% ethyl acetate/hexaneto afford 5-bromo-3-((tert-butyldimethylsilyloxy)methyl)isothiazole as apale yellow liquid. MS (ESI pos. ion) m/z: 308.0 and 310.0 (MH⁺).

5)3-((tert-butyldimethylsilyloxy)methyl)-5-(trimethylstannyl)isothiazole.5-Bromo-3-((tert-butyldimethylsilyloxy)methyl)isothiazole (0.100 g,0.324 mmol) was dissolved in THF (1 mL) then cooled to −78° C. and added1.6 M n-BuLi in hexane (0.223 ml, 0.357 mmol) dropwise via syringe. Thereaction mixture became yellow and stirring was continued at −78° C. for45 minutes. 1M Trimethyltin chloride in THF (0.324 ml, 0.324 mmol) wasadded to the mixture dropwise via syringe. No color change was observed.Continued stirring at −78° C. for 1.5 hours. The reaction was quenchedwith saturated aqueous sodium bicarbonate at −78° C. then warmed to roomtemperature. The mixture was diluted with water then extracted withether. The organic layer was dried over sodium sulfate and concentratedunder vacuum to afford3-((tert-butyldimethylsilyloxy)methyl)-5-(trimethylstannyl)isothiazole(0.121 g, 95.1% yield) as a light yellow liquid.

6)bis(1,1-dimethylethyl)(6-(3-((((1,1-dimethylethyl)(dimethyl)silyl)oxy)methyl)-5-isothiazolyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylimidodicarbonate.Bis(1,1-dimethylethyl)(6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylimidodicarbonate(0.200 g, 0.521 mmol) was suspended in dioxane (3 mL) then added3-((tert-butyldimethylsilyloxy)methyl)-5-(trimethylstannyl)isothiazole(0.429 g, 1.09 mmol), xantphos (0.0301 g, 0.0521 mmol), palladium (II)acetate (0.00585 g, 0.0261 mmol), and water (0.0188 ml, 1.04 mmol). Thereaction mixture was heated at 100° C. for 3 hours. The reaction mixturewas concentrated under vacuum. The sample was purified by flashchromatography eluting with 0-100% ethyl acetate to affordbis(1,1-dimethylethyl)(6-(3-((((1,1-dimethylethyl)(dimethyl)silyl)oxy)methyl)-5-isothiazolyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylimidodicarbonate(0.170 g, 56.6% yield) as a yellow oil. MS (ESI pos. ion) m/z: 577.2(MH⁺).

7)(5-(3-(aminomethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)isothiazol-3-yl)methanol.Bis(1,1-dimethylethyl)(6-(3-((((1,1-dimethylethyl)(dimethyl)silyl)oxy)methyl)-5-isothiazolyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylimidodicarbonate(0.170 g, 0.29 mmol) was dissolved in ethyl acetate (5 mL) thenhydrochloric acid gas was bubbled through the mixture for approx. 5minutes. A precipitate formed and stirring was continued at roomtemperature for 1.5 hours. The reaction was concentrated under vacuumthen mostly redissolved in methanol (3.5 mL) and added ammoniumhydroxide (0.052 ml, 1.3 mmol). The mixture was stirred at roomtemperature for 2 hours then concentrated under vacuum. The sample waspurified by flash chromatography eluting with 50-100% 90:10:1dichloromethane/methanol/NH4OH followed by 100% 90:10:1dichloromethane/methanol/NH4OH to afford(5-(3-(aminomethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)isothiazol-3-yl)methanol(0.066 g, 85% yield) as a white solid. MS (ESI pos. ion) m/z: 263.0(MH⁺).

EXAMPLE 4376-((8-fluoro-6-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)quinoline

1)6-((6-chloro-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)quinoline.A mixture of 1-(5-chloro-3-fluoropyridin-2-yl)hydrazine (500 mg, 3095μmol) and methyl 2-(quinolin-6-yl)acetate (600 mg, 2982 μmol) in HCl(conc., 600 μL, 7200 μmol) was heat at 100° C. for 20 min. The mixturewas then heated in a microwave at 180° C. for 40 min. The mixture wasquenched with NaOH (5 N, 1.5 mL) and the suspension was filtered andwashed with H₂O. The resulting brown solid is mostly the desiredproduct. The solid was then triturated with NaOH (5 N, 1 mL), filtered,and washed with H₂O. LCMS (ESI pos. ion): calc'd for C₁₆H₁₀ClFN₄: 312.0;found: 313.1 (M+1).

2)6-((8-fluoro-6-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)quinoline.A mixture of Pd(OAc)₂ (6.46 mg, 28.8 μmol), potassium phosphate (367 mg,1727 μmol), phenylboronic acid (211 mg, 1727 μmol),dicyclohexyl(2-(2,4,6-triisopropylcyclohexa-1,3-dienyl)phenyl)phosphine(27.6 mg, 57.6 μmol), and6-((6-chloro-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)quinoline(180 mg, 576 μmol) in dioxane (6 mL)-H₂O (2 mL) was heated to 100° C.under nitrogen for 20 h. The mixture was cooled to rt and partitionedbetween H₂O and CH₂Cl₂. The organic layer was dried over MgSO₄ andconcentrated. The residual was purified on silica using MeOH in DCM(0-5%) to give a pink solid. This solid was triturated withhexane-EtOAc-DCM (hot) to give a brown solid (105 mg). LCMS (ESI pos.ion): calc'd for C₂₂H₁₅FN₄: 354.1; found: 355.2 (M+1).

EXAMPLE 4386-((8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)quinolin-3-ol

A mixture of crude6-((6-chloro-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-3-methoxyquinoline(200 mg, 584 μmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(600 mg, 2884 μmol), PdCl₂(dppf)-CH₂Cl₂ adduct (24 mg, 29 μmol), andNa₂CO₃ (500 mg, 4717 μmol) in DME (7 mL)-H₂O (5 mL) was heated at 100°C. under nitrogen. After overnight, the sludge was treated with DMSO (10mL) and filtered. The DMSO solution was purified on HPLC (10-60%/10min). The product fraction was concentrated to dryness with toluene. Thesolid was then triturated with MeOH-hexane (1:2) to give a brown powder(60 mg). LCMS (ESI pos. ion): calc'd for C₂₀H₁₅FN₆O: 374.1. found 375.1(M+1).

EXAMPLE 4396-((5-(3,5-difluorophenyl)isoxazolo[5,4-b]pyridin-3-yl)difluoromethyl)quinoline

1) 2,2-difluoro-2-(quinolin-6-yl)acetic acid. To a solution of methyl2,2-difluoro-2-(quinolin-6-yl)acetate (2.0 g, 8.4 mmol) in dioxane (4mL) and water (12 mL) was added lithium hydroxide monohydrate (0.53 g,12 mmol). After stirring at 50° C. for thirty minutes, the solution wasbrought to pH 4 with 2.0 N HCl. The solution was concentrated and driedon a lyophilizer overnight to yield the product as an orange solid. MSm/z=224.0 [M+1

2) 2,2-difluoro-2-(quinolin-6-yl)acetyl chloride hydrochloride. To asuspension of 2,2-difluoro-2-(quinolin-6-yl)acetic acid (1.9 g, 8.4mmol) in dichloromethane (16 mL) was added oxalyl chloride (7.4 mL, 84mmol). The mixture was stirred at 45° C. for one hour. The suspensionwas filtered and the resulting filtrate concentrated to yield theproduct as an orange oil (1.8 g, 73% step 1 and 2 combined).

3)1-(5-bromo-2-fluoropyridin-3-yl)-2,2-difluoro-2-(quinolin-6-yl)ethanone.To a solution of 3,5-dibromo-2-fluoropyridine (3.1 g, 12 mmol) inanhydrous THF (12 mL) under argon was added isopropylmagnesium chloride(2.0 M in THF, 6.0 mL, 12 mmol). The solution was stirred at roomtemperature for ten minutes, then was added via cannula to a solution of2,2-difluoro-2-(quinolin-6-yl)acetyl chloride hydrochloride (1.8 g, 6.1mmol) in anhydrous THF (20 mL) at −78° C. The solution was allowed torise to −40° C. over one hour; then was stirred at 0° C. for one hour.The reaction was quenched with water and extracted with ethyl acetate;organic extracts were dried over magnesium sulfate and concentrated.Purification by MPLC (eluted with a gradient of 20 to 80% ethyl acetatein hexanes) afforded the product as a tan solid (0.90 g, 38%).

4)1-(5-bromo-2-fluoropyridin-3-yl)-2,2-difluoro-2-(quinolin-6-yl)ethanoneoxime. To a pressure vessel was added hydroxylamine hydrochloride (1.6g, 24 mmol), sodium acetate (2.9 g, 35 mmol) and1-(5-bromo-2-fluoropyridin-3-yl)-2,2-difluoro-2-(quinolin-6-yl)ethanone(0.90 g, 2.4 mmol) in acetic acid (20 mL). The suspension was sealed andstirred at 100° C. for fifteen minutes, then was concentrated,triturated with water and filtered. Purification of the resulting solidby MPLC (eluted with a gradient of 0-10% methanol in dichloromethane)afforded the product as a beige solid (0.59 g, 63%). MS m/z=396.0 [M+1]⁺

5) 6-((5-bromoisoxazolo[5,4-b]pyridin-3-yl)difluoromethyl)quinoline. Toa solution of1-(5-bromo-2-fluoropyridin-3-yl)-2,2-difluoro-2-(quinolin-6-yl)ethanoneoxime (0.59 g, 1.5 mmol) in anhydrous THF (10 mL) was added sodiumhydride (0.090 g, 2.3 mmol) at 0° C. After ten minutes, the solution wasdiluted with ethyl acetate and washed with water, organic extracts weredried over magnesium sulfate. Purification by MPLC (eluted with agradient of 20-50% ethyl acetate in hexanes) afforded the product as awhite solid (0.39 g, 70%). MS m/z=377.0 [M+1]⁺ Calc'd for C₁₆H₈BrF₂N₃O:376.2

6)6-((5-(3,5-difluorophenyl)isoxazolo[5,4-b]pyridin-3-yl)difluoromethyl)quinoline.To a pressure vessel was added PdCl₂(dppf)-CH₂Cl₂ adduct (0.0076 g,0.0093 mmol), cesium carbonate (0.13 g, 0.40 mmol),6-((5-bromoisoxazolo[5,4-b]pyridin-3-yl)difluoromethyl)quinoline (0.050g, 0.13 mmol) and 3,5-difluorophenylboronic acid (0.031 g, 0.020 mmol)in DMF (1.0 mL) water (0.25 mL). The vessel was purged with argon,sealed and stirred at 80° C. for two hours. The mixture wasconcentrated, triturated with water an filtered; purification of theresulting precipitate by MPLC (eluted with a gradient of 20 to 50% ethylacetate in hexanes afforded the product as a white solid (27 mg, 53%).

EXAMPLE 4406-(difluoro(5-(1-methyl-1H-pyrazol-4-yl)isoxazolo[4,5-b]pyridin-3-yl)methyl)quinoline

1) 2,2-difluoro-N-methoxy-N-methyl-2-(quinolin-6-yl)acetamide. To asolution of N-methoxymethanamine hydrochloride (3.7 g, 38 mmol) andmethyl 2,2-difluoro-2-(quinolin-6-yl)acetate (6.0 g, 25 mmol) inanhydrous THF (30 mL) was added isopropylmagnesium chloride (2.0 M, 38mL, 76 mmol) at −20° C. After thirty minutes the reaction was quenchedwith saturated ammonium chloride and extracted with diethyl ether;organic extracts were dried over magnesium sulfate. Purification by MPLC(eluted with a gradient of 10 to 70% ethyl acetate in hexanes) affordedthe product as an orange solid. MS m/z=267.2 [M+1]⁺.

2)1-(6-chloro-3-fluoropyridin-2-yl)-2,2-difluoro-2-(quinolin-6-yl)ethanone.n-Butyllithium (2.5M in hexanes, 3.70 ml, 9.25 mmol) was added to astirred solution of DABCO (1.04 g, 9.25 mmol) in Et₂O (46 mL) at −78° C.The reaction mixture was stirred 1 h at −20° C. and then cooled again at−78° C. 2-Chloro-5-fluoropyridine (0.939 ml, 9.25 mmol) in Et₂O (5 mL)was added. Stirring was continued at −78° C. for 1 h.2,2-Difluoro-N-methoxy-N-methyl-2-(quinolin-6-yl)acetamide (2.24 g, 8.41mmol) in Et₂O (20 mL) was added by cannula. The reaction mixture wasstirred at −78° C. for 70 min. The cooling bath was replaced by anice/water bath. After 10 min of stirring at 0° C., the reaction mixturewas quenched with water. The water layer was extracted with EtOAc andDCM/MeOH(9/1). The organic layers were combined, dried over MgSO₄,filtered and concentrated in vacuo. Purification by MPLC (hexanes/EtOAc:100/0 to 40/60) afforded the title compound (2.27 g, 80% yield).

3)1-(6-chloro-3-fluoropyridin-2-yl)-2,2-difluoro-2-(quinolin-6-yl)ethanoneoxime. To a pressure vessel was added1-(6-chloro-3-fluoropyridin-2-yl)-2,2-difluoro-2-(quinolin-6-yl)ethanone(1.0 g, 3.0 mmol), sodium acetate (3.7 g, 45 mmol) and hydroxylaminehydrochloride (2.1 g, 30 mmol) in acetic acid (15 mL). The vessel wassealed and the suspension was stirred at 100° C. for twenty minutes.Following concentration and trituration with water, a white precipitatewas collected via filtration. Purification of the solid by MPLC (elutedwith 0-10% methanol in dichloromethane) afforded the product as a whitesolid (0.85 g, 82%) MS m/z=352.0 [M+1]⁺.

4) 6-((5-chloroisoxazolo[4,5-b]pyridin-3-yl)difluoromethyl)quinoline. Toa pressure vessel was added1-(6-chloro-3-fluoropyridin-2-yl)-2,2-difluoro-2-(quinolin-6-yl)ethanoneoxime (0.050 g, 0.14 mmol) and cesium carbonate (0.14 g, 0.43 mmol) inanhydrous DMF (1 mL). After stirring at 80° C. for 30 minutes, thesolution was diluted with ethyl acetate and washed with water. Organicextracts were dried over magnesium sulfate and purified by MPLC (elutedwith a gradient of 10 to 50% ethyl acetate in hexanes) to yield theproduct as a white solid (35 mg, 74%) MS m/z=332.2 [M+1]⁺. Calc'd forC16H8ClF2N3O: 331.7.

5)6-(difluoro(5-(1-methyl-1H-pyrazol-4-yl)isoxazolo[4,5-b]pyridin-3-yl)methyl)quinoline.To a pressure vessel was added6-((5-chloroisoxazolo[4,5-b]pyridin-3-yl)difluoromethyl)quinoline) (0.10g, 0.30 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (0.012 g, 0.015 mmol), cesiumcarbonate (0.29 g, 0.90 mmol) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.094 g, 0.45 mmol) in DMF (2 mL) and water (0.5 mL). The vessel waspurged with argon, sealed and stirred at 80° C. for forty minutes. Themixture was diluted with ethyl acetate and washed with water, organicextracts were dried over magnesium sulfate. Purification by MPLC (elutedwith a gradient of 0 to 10% methanol in dichloromethane) afforded theproduct as a light yellow solid (45 mg, 40%). MS m/z=378.2 [M+1]⁺ Calc'dfor C₂₀H₁₃F₂N₅O: 377.3.

EXAMPLE 4416-((R)-1-(5-(1-methyl-1H-pyrazol-4-yl)isoxazolo[5,4-b]pyridin-3-yl)ethyl)quinoline

1) Methyl 2-(quinolin-6-yl)propanoate. To a solution of methyl2-(quinoline-6-yl)acetate (7.0 g, 35 mmol) in anhydrous THF (70 mL) wasadded lithium bis(trimethylsilyl)amide (1.0 M in THF, 35 mL, 35 mmol)and solution of methyl iodide (2.2 mL, 35 mmol) in anhydrous THF (1 mL)at −78° C. The dry ice in acetone bath was removed and the mixture wasstirred for 35 minutes, then was quenched with saturated ammoniumchloride (30 mL), diluted with ethyl acetate and washed with saturatedsodium bicarbonate. Organic extracts were dried over magnesium sulfateand purified via MPLC (eluted with a gradient of 10 to 30% ethyl acetatein hexanes) to yield the product as a light yellow oil (6.5 g, 87%).

2) 2-(quinolin-6-yl)propanoic acid. To a solution of methyl2-(quinolin-6-yl)propanoate (1.4 g, 6.5 mmol) in methanol (7 mL) andwater (1.5 mL) was added sodium hydroxide (6 N, 2.7 mL, 16 mmol) and thesolution was stirred at 50° C. for one hour. The solution wasconcentrated, brought to pH 4 with 2.0 N HCl and the product wasisolated via filtration as a white solid (0.94 g, 72%).

3) 2-(quinolin-6-yl)propanoyl chloride hydrochloride. To a suspension of2-(quinolin-6-yl)propanoic acid (0.73 g, 3.6 mmol) in anhydrousdichloromethane (15 mL) was added thionyl chloride (1.3 mL, 18 mmol) andthe solution was stirred at room temperature for ten minutes. Thesolution was concentrated to yield the product as an orange solid.

4) 1-(5-bromo-2-fluoropyridin-3-yl)-2-(quinolin-6-yl)propan-1-one. To asolution of 3,5-dibromo-2-fluoropyridine (2.4 g, 9.3 mmol) in anhydrousTHF (10 mL) was added isopropylmagnesium chloride (2.0 M in THF, 4.7 mL,9.3 mmol) and stirred at room temperature for ten minutes. The solutionwas added via cannula to a solution of 2-(quinolin-6-yl)propanoylchloride hydrochloride (0.79 g, 3.1 mmol) in anhydrous THF (10 mL) at−78° C. and the combined reaction mixture was allowed to rise to −40° C.over one hour. The mixture was stirred at −40° C. for an additional 90minutes, then was quenched with saturated sodium bicarbonate andextracted with ethyl acetate. Organic extracts were dried over magnesiumsulfate and purified via MPLC (eluted with a gradient of 10-80% ethylacetate in hexanes) to yield the product as a yellow oil (0.60 g, 54%).

5) 1-(5-bromo-2-fluoropyridin-3-yl)-2-(quinolin-6-yl)propan-1-one oxime.To a pressure vial was added sodium acetate (2.0 g, 24 mmol),hydroxylamine hydrochloride (1.1 g, 16 mmol) and1-(5-bromo-2-fluoropyridin-3-yl)-2-(quinolin-6-yl)propan-1-one (0.58 g,1.6 mmol) in acetic acid (10 mL). The vial was sealed and stirred at100° C. for one hour, then was concentrated, diluted with ethyl acetateand washed with water. Organic extracts were concentrated and purifiedby MPLC (eluted with 0-10% methanol in dichloromethane) to yield theproduct as a tan oil (0.50 g, 83%).

6) 6-(1-(5-bromoisoxazolo[5,4-b]pyridin-3-yl)ethyl)quinoline. To asolution of1-(5-bromo-2-fluoropyridin-3-yl)-2-(quinolin-6-yl)propan-1-one oxime(0.58 g, 1.6 mmol) in THF (15 mL) was added sodium hydride (60% inmineral oil, 0.093, 2.3 mmol) at 0° C. The solution was stirred at 0° C.for ten minutes, then was diluted with ethyl acetate and washed withwater. Organic extracts were concentrated and purified by MPLC (elutedwith a gradient of 10 to 50% ethyl acetate in hexanes) to yield theproduct as a colorless oil (0.10 g, 19%). MS m/z=354.0 [M+1]⁺. Calc'dfor C₁₇H₁₂BrN₃O: 354.2

7)6-((R)-1-(5-(1-methyl-1H-pyrazol-4-yl)isoxazolo[5,4-b]pyridin-3-yl)ethyl)quinoline.To a pressure vial was added6-(1-(5-bromoisoxazolo[5,4-b]pyridin-3-yl)ethyl)quinoline (0.09 g, 0.25mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (0.010 g, 0.013 mmol), cesium carbonate(0.25 g, 0.76 mmol) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.079 g, 0.38 mmol) in DMF (2.5 mL) and water (0.5 mL). The vessel wasflushed with argon, sealed and stirred at 90° C. for one hour. Themixture was concentrated, triturated in water and a brown solid wascollected via filtration. Purification by MPLC (eluted with a gradientof 10 to 50% ethyl acetate) afforded a racemic mixture of the product.The desired enantiomer (>99% ee) was obtained via SFC. MS m/z=356.2[M+1]⁺ Calc'd for C₂₁H₁₇N₅O: 355.4

EXAMPLE 442

N-((6-(3-(fluoromethyl)isoxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine:To a suspension of(5-(3-((7-methoxy-1,5-naphthyridin-4-ylamino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)isoxazol-3-yl)methanol(0.080 g, 0.20 mmol) in anhydrous dichloromethane (3 mL) was addeddeoxofluor (0.10 mL, 0.060 mmol) under argon at 0° C. The solution wasbrought to room temperature over one hour and stirred three additionalhours. The reaction was quenched with saturated sodium bicarbonate andstirred for 15 minutes; a brown gum was collected by filtration.Purification via MPLC (eluted with a gradient of 0 to 10% methanol indichloromethane) afforded the product as an off-white solid (9.0 mg,11%). MS m/z=407.2[M+1]⁺. Calc'd for C₁₉H₁₅FN₈O₂: 406.4

EXAMPLE 4436-(difluoro(5-(3-methylisothiazol-5-yl)isoxazolo[5,4-b]pyridin-3-yl)methyl)quinoline

To a pressure vial was added 2-(dicyclohexylphosphino)biphenyl (9.3 mg,0.013 mmol),6-((5-bromoisoxazolo[5,4-b]pyridin-3-yl)difluoromethyl)quinoline (0.10g, 0.27 mmol), 3-methyl-5-(trimethylstannyl)isothiazole (0.14 g, 0.53mmol) and Pd₂(dba)₃ (12 mg, 0.013 mmol) in anhydrous DMF (5 mL). Thevessel was purged with argon, sealed and stirred at 80° C. for ninetyminutes. The mixture was concentrated and purified by MPLC (eluted witha gradient of 10 to 50% ethyl acetate in hexanes) to yield the productas a light yellow solid. MS m/z=395.0 [M+1]⁺ Calc'd for C₂₀H₁₂F₂N₄OS:394.4.

The following example compounds 444-448 were prepared using a methodsimilar to6-(difluoro(5-(3-methylisothiazol-5-yl)isoxazolo[5,4-b]pyridin-3-yl)methyl)quinoline:

Mass Ex Structure MW Found 444

374 375 445

380 381 446

378 379 447

363 364 448

377 378

EXAMPLE 449N-cyclobutyl-3-(difluoro(quinolin-6-yl)methyl)isoxazolo[5,4-b]pyridin-5-amine

To a pressure vial was added sodium tert-butoxide (38 mg, 0.40 mmol),xantphos (0.12 g, 0.20 mmol), Pd₂(dba)₃ (61 mg, 0.066 mmol),6-((5-bromoisoxazolo[5,4-b]pyridin-3-yl)difluoromethyl)quinoline (0.10g, 0.27 mmol), and cyclobutanamine (0.025 mL, 0.29 mmol) in toluene (3mL). The mixture was stirred at 80° C. for two hours then was dilutedwith dichloromethane and filtered through celite. Purification of thefiltrate by MPLC (eluted with a gradient of 10 to 50% ethyl acetate inhexanes) afforded the product as a yellow oil (5.1 mg, 5%). MS m/z=367.0[M+1]⁺ Calc'd for C₂₀H₁₆F₂N₄O: 366.4

EXAMPLE 4506-((5-(3,5-difluorophenyl)isoxazolo[5,4-b]pyridin-3-yl)difluoromethyl)quinoline

To a pressure vessel was added cesium carbonate (0.61 g, 1.9 mmol),PdCl₂(dppf)-CH₂Cl₂ adduct (26 mg, 0.031 mmol),1-(6-chloro-3-fluoropyridin-2-yl)-2,2-difluoro-2-(quinolin-6-yl)ethanoneoxime (0.26 g, 0.63 mmol) and 3,5-difluorophenylboronic acid (0.15 g,0.94 mmol) in anhydrous DMF (5 mL) and water (1 mL). The mixture flushedwith argon, sealed and stirred at 80° C. for one hour. The suspensionwas concentrated, triturated with water and filtered to afford a tansolid, purification by MPLC (eluted with a gradient of 20 to 50% ethylacetate in hexanes) afforded the product as a white solid (23 mg, 9%).MS m/z=410.0 [M+1]⁺ Calc'd for C₂₂H₁₁F₄N₃O: 409.3.

EXAMPLE 4516-(difluoro(5-(3-methylisothiazol-5-yl)isoxazolo[4,5-b]pyridin-3-yl)methyl)quinoline

To a solution of 5-bromo-3-methylisothiazole (0.19 g, 1.1 mmol) inanhydrous THF (3 mL) was added isopropylmagnesium lithium chloride (1.0M in THF, 1.5 mL, 1.5 mmol) at −40° C. The mixture was stirred at −40°C. for twenty minutes followed by the addition of zinc chloride (0.5 Min THF, 3.1 mL, 1.6 mmol). The mixture was brought to room temperatureand stirred for thirty minutes followed by the addition of Q-Phos (0.12g, 0.17 mmol), Pd₂(dba)₃ (0.097 g, 0.110 mmol),6-((5-chloroisoxazolo[4,5-b]pyridin-3-yl)difluoromethyl)quinoline (0.10g, 0.30 mmol), and anhydrous dimethylacetamide (3.5 mL). The mixture wasstirred at 50° C. for ninety minutes then was diluted with ethyl acetateand washed with water. Organic extracts were dried over magnesiumsulfate and purified by MPLC (eluted with a gradient of 10 to 50% ethylacetate in hexanes), then purified by HPLC (eluted with a gradient of 15to 90% acetonitrile in water) to afford the product as a white solid(4.2 mg, 3%). MS m/z=395.2 [M+1]⁺Calc'd for C₂₃H₁₅F₂N₃O: 394.4.

EXAMPLE 4523-(difluoro(quinolin-6-yl)methyl)-N,N-dimethylisoxazolo[4,5-b]pyridin-5-amine

To a microwave vial was added dimethylamine (2.0 M in THF, 0.75 mL, 1.5mmol) and,6-((5-chloroisoxazolo[4,5-b]pyridin-3-yl)difluoromethyl)quinoline (0.10g, 0.30 mmol) in ethanol (3 mL). The mixture was stirred at 140° undermicrowave irradiation for two hours then was concentrated and purifiedby MPLC (eluted with a gradient of 10 to 50% ethyl acetate in hexanes)to yield the product as a light yellow solid (87 mg, 85%). MS m/z=341.2[M+1]⁺ Calc'd for C₁₈H₁₄F₂N₄O: 340.3.

Mass Ex Structure MW Found Method 453

387 388 H 454

387 388 H

EXAMPLE 4556-(1-(5-(thiazol-4-yl)isoxazolo[5,4-b]pyridin-3-yl)ethyl)quinoline

To a pressure vessel was added 2-(dicyclohexylphosphino)biphenyl (12 mg,0.42 mmol), 6-(1-(5-bromoisoxazolo[5,4-b]pyridin-3-yl)ethyl)quinoline(0.10 g, 0.28 mmol), and 4-(tributylstannyl)thiazole (0.16 g, 0.42 mmol)in anhydrous DMF (3 mL). The vial was flushed with argon, sealed andstirred at 90° C. for two hours. The mixture was concentrated andpurified by MPLC (eluted with a gradient of 0 to 10% methanol indichloromethane) to afford the product as an off-white solid. MSm/z=359.0 [M+1]⁺ Calc'd for C₂₀H₁₄N₄OS: 358.4.

EXAMPLE 4566-((R)-1-(5-(thiazol-4-yl)isoxazolo[5,4-b]pyridin-3-yl)ethyl)quinoline

To a pressure vessel was added 2-(dicyclohexylphosphino)biphenyl (12 mg,0.42 mmol), 6-(1-(5-bromoisoxazolo[5,4-b]pyridin-3-yl)ethyl)quinoline(0.10 g, 0.28 mmol), 4-(tributylstannyl)thiazole (0.16 g, 0.42 mmol) inanhydrous DMF (3 mL). The vial was flushed with argon, sealed andstirred at 90° C. for two hours. The mixture was concentrated andpurified by MPLC (eluted with a gradient of 0 to 10% methanol indichloromethane) to yield the racemic product as an off-white solid. Thedesired enantiomer (>99% ee) was obtained via SFC. MS m/z=359.0 [M+1]⁺Calc'd for C₂₀H₁₄N₄OS: 358.4

EXAMPLE 4576-((S)-1-(5-(thiazol-4-yl)isoxazolo[5,4-b]pyridin-3-yl)ethyl)quinoline

Prepared by a method similar to6-((R)-1-(5-(thiazol-4-yl)isoxazolo[5,4-b]pyridin-3-yl)ethyl)quinoline.MS m/z=359.0 [M+1]⁺ Calc'd for C₂₀H₁₄N₄OS: 358.4.

EXAMPLE 4586-((S)-1-(5-(1-methyl-1H-pyrazol-4-yl)isoxazolo[5,4-b]pyridin-3-yl)ethyl)quinoline

Prepared by a method similar to6-((R)-1-(5-(1-methyl-1H-pyrazol-4-yl)isoxazolo[5,4-b]pyridin-3-yl)ethyl)quinoline.MS m/z=356.2 [M+1]⁺ Calc'd for C₂₁H₁₇N₅O: 355.4

EXAMPLE 4597-methoxy-4-((6-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)quinoline

To a solution of tert-butyl2-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate(0.27 g, 0.50 mmol) (prepared according to general method A) was addedtrifluoroacetic acid (0.77 mL, 10 mmol). The mixture was stirred at roomtemperature for 90 minutes, then was concentrated, taken up in 2.0 Mammonia in methanol and purified by MPLC (eluted with a gradient of 0 to10% methanol in dichloromethane) to yield the product as a pink solid.MS m/z=445.0 [M+1]⁺ Calc'd for C₂₃H₂₀N₆O₂S: 444.51.

5-bromo-N,N-dimethylthiazol-2-amine: To a microwave vial was addedN-ethyl-N-isopropylpropan-2-amine (0.72 mL, 4.1 mmol),2,5-dibromothiazole (1.00 g, 4.1 mmol) and dimethylamine (40% in water,0.52 mL, 4.1 mmol) in ethanol (10 mL). The vial was sealed and stirredat 140° C. under microwave irradiation for one hour, then wasconcentrated and purified by MPLC (eluted with a gradient of 0-50% ethylacetate in hexanes) to yield the product as a white, crystalline solid(0.25 g, 29%).

tert-butyl(6-(2-(dimethylamino)thiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate:To a solution of 5-bromo-N,N-dimethylthiazol-2-amine (0.73 g, 3.53 mmol)in anhydrous THF (9 mL) was added isopropylmagnesium lithium chloride(1.0 M in THF, 4.8 mL, 4.8 mmol) at −40° C. The solution was stirred fortwenty minutes followed by the dropwise addition of zinc chloride (0.5 Min THF, 10 mL, 5.2 mmol). The mixture was brought to room temperatureand stirred for thirty minutes followed by the addition ofdimethylacetamide (12 mL), Pd₂(dba)₃, (0.32 g, 0.35 mmol), Q-Phos (0.34g, 0.56 mmol), and tert-butyl(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (0.29 g,1.0 mmol). The mixture was stirred at 50° for two hours then wasquenched with saturated ammonium chloride and purified by MPLCchromatography (eluted with a gradient of 0 to 10% (1:10:90NH₄OH:MeOH:DCM) in DCM) to yield the product as a light orange solid(0.27 g, 71%).

EXAMPLE 4606-(difluoro(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-3-methoxyquinoline

1) tert-butyl 2,2-difluoro-2-(3-methoxyquinolin-6-yl)acetate. The titlecompound was made from tert-butyl 2-(3-methoxyquinolin-6-yl)acetate in asimilar fashion to the procedure reported for the synthesis of methyl2,2-difluoro-2-(quinolin-6-yl)acetate.

2) 2,2-difluoro-2-(3-methoxyquinolin-6-yl)acetic acid. A 200 mL roundbottom flask was charged with tert-butyl2,2-difluoro-2-(3-methoxyquinolin-6-yl)acetate (5.06 g, 16 mmol) thenCH₂Cl₂, then trifluoroacetic acid (16 ml, 213 mmol) followed bytriethylsilane (6.5 ml, 41 mmol). The solution was maintained at rt for24 h until LCMS showed disappearance of starting material. The solutionwas concentrated and was subjected to high vacuum for 40 h to give 4.1 g(99% yield) of 2,2-difluoro-2-(3-methoxyquinolin-6-yl)acetic acid as abrown solid. The material was of sufficient purity for use in subsequentsteps.

3) 2,3-difluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridine. A sealable flaskwas charged with 5-chloro-2,3-difluoropyridine (1.541 g, 10.3 mmol),palladium(ii) acetate (0.116 g, 0.515 mmol), potassium phosphatetribasic (6.56 g, 30.9 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(2.57 g, 12.4 mmol), and X-Phos (0.491 g, 1.03 mmol). The flask wassealed with a septum cap, then dioxane (20 mL) and H2O (2 mL) wereadded. The resulting mixture was sparged with N₂ for 10 min, and thenheated at 100° C. for 2 h. The solution was cooled to rt and thenconcentrated and purified by flash chromatography using eluent 99:1Hexanes:EtOAc to 60:40 Hexanes:EtOAc gradient to afford2,3-difluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridine (1.78 g, 88.5% yield)as a colorless film. LRMS (ESI) m/z calcd for C₉H₇F₂N₃ (M+H) 197.1.found 197.4.

4)2,2-difluoro-N′-(2-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenyl)-2-(3-methoxyquinolin-6-yl)acetohydrazide.A round bottom flask was charged with2,2-difluoro-2-(3-methoxyquinolin-6-yl)acetic acid (389 mg, 1536 μmol)and DMF (8 mL). The solution was cooled to 0 C, thionyl chloride (224μl, 3073 μmol), was added and the resulting solution was maintained 1 hat 0° C. Then, triethylamine (641 μl, 4609 μmol) was added via syringe,followed by1-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)hydrazine (382 mg,1844 μmol) and 4-(dimethylamino)pyridine (18.8 mg, 154 μmol); both addedas solids. The heterogeneous solution was stirred at 0° C. for 1 h, thenallowed to warm to rt and stir for 18 h. The mixture was quenched withsaturated aqueous NaHCO₃ (50 mL) and the resulting mixture was extractedwith CH₂Cl₂ (3×50 mL). The combined organic layers were concentrated(heating to 50° C.) and the residue purified by SiO₂ chromatographysolvent system: CH₂Cl₂:MeOH 99%:1% gradient 90:10 CH₂Cl₂ to yield2,2-difluoro-N′-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-(3-methoxyquinolin-6-yl)acetohydrazide(225 mg, 33.1% yield) as a brown amorphous solid.

5)6-(difluoro(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-3-methoxyquinoline.A sealable microwave vial was charged with2,2-difluoro-N′-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-(3-methoxyquinolin-6-yl)acetohydrazide(225 mg, 509 μmol) and polymer supported triphenylphosphine (2.3 mmol/g,221 mg, 509 μmol). The flask was sealed and dichloroethane (4 mL) wasadded followed by diisopropylethylamine (89 μl, 509 μmol) and2,2,2-trichloroacetonitrile (127 μl, 1271 μmol). The resulting mixturewas irradiated in a microwave (Biotage Initiator) at 150° C. for 40 min.The reaction mixture was filtered and the filter cake was washed withCH₂Cl₂ (15 mL) and MeOH (10 mL). The filtrate was concentrated in vacuoand the resulting crude residue was purified by MPLC using 100% CH₂Cl₂to 98:2 CH₂Cl₂:MeOH to afford6-(difluoro(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-3-methoxyquinoline(94 mg, 44% yield) as a tan amorphous solid. LRMS (ESI) m/z calcd forC₂₁H₁₆F₃N₆O (M+H) 425.1. found 425.4.

EXAMPLE 4616-(difluoro(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)quinolin-3-ol

To a flask charged with3-(benzyloxy)-6-(difluoro(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)quinoline(10 mg, 20 μmol) was added trifluoroacetic acid (1.5 mL, 20 mmol). Theresulting solution was heated at 65° C. for 18 h. The solution wasconcentrated for purification by MPLC using 98:2 CH₂Cl₂:MeOH to 90:10CH₂Cl₂:MeOH gradient to afford6-(difluoro(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)quinolin-3-ol(3.6 mg, 44% yield) as a colorless solid. LRMS (ESI) m/z calcd forC₂₀H₁₄F₃N₆O (M+H) 411.1. found 411.3.

EXAMPLE 4626-(difluoro(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-3-(3-morpholinopropoxy)quinoline

To a flask charged with6-(difluoro(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)quinolin-3-ol(17.3 mg, 42 μmol), was added triphenylphosphine (55 mg, 211 μmol), THF(1 mL), and 4-(3-hydroxypropyl)-morpholine, 95% (31 μl, 211 μmol). Themixture was placed under N₂ and cooled to 0° C. Di-tert-butylazodicarboxylate (49 mg, 211 μmol) was added as a solid in a singleportion and the solution was allowed to warm to rt and was maintainedfor 48 h. The solution was concentrated for purification by MPLC(Teledine Isco combiFlash Companion). The crude residue was taken up inminimal CH₂Cl₂ and absorbed onto a 5 g loading cartridge and passedthrough a Redi-Sep® pre-packed silica gel column (40 g) using 99:1CH₂Cl₂:MeOH to 90:10 CH₂Cl₂:MeOH gradient to afford6-(difluoro(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-3-(3-morpholinopropoxy)quinoline(7.5 mg, 33% yield) as a colorless solid.; LRMS (ESI) m/z calcd forC₂₇H₂₇F₃N₇O₂ (M+H) 538.2. found 538.2.

EXAMPLE 4636-((6-(3,5-difluorophenyl)-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)-3-methoxyquinoline

a)N′-(5-chloro-3-fluoropyridin-2-yl)-2,2-difluoro-2-(3-methoxyquinolin-6-yl)acetohydrazide.This compound was assembled from2,2-difluoro-2-(3-methoxyquinolin-6-yl)acetic acid and1-(5-chloro-3-fluoropyridin-2-yl)hydrazine according to General MethodI. LRMS (ESI) m/z calcd for C₁₇H₁₃ClF₃N₄O₂S (M+H) 397.1. found 397.2.

b)6-((6-chloro-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)-3-methoxyquinoline.This compound was made fromN′-(5-chloro-3-fluoropyridin-2-yl)-2,2-difluoro-2-(3-methoxyquinolin-6-yl)acetohydrazideaccording to General Method I. LRMS (ESI) m/z calcd for C₁₇H₁₁ClF₃N₄O(M+H) 379.1. found 379.2.

c)6-((6-(3,5-difluorophenyl)-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)-3-methoxyquinoline.A sealable microwave vial was charged with6-((6-chloro-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)-3-methoxyquinoline(342.05 mg, 903 μmol), palladium(II) acetate (30 mg, 135 μmol),potassium phosphate (575 mg, 2709 μmol), 3,5-difluorophenylboronic acid(285 mg, 1806 μmol), and X-Phos (129 mg, 271 μmol). The tube was sealed,and flushed with N₂. Dioxane (9 mL), then H₂O (1 mL) were added and themixture was sparged with N₂ for 10 min, then heated at 100° C. for 24 h.The mixture was cooled to rt and concentrated absorbed onto a 5 gloading cartridge for MPLC purification using a 98:2 CH₂Cl₂:MeOH to90:10 CH₂Cl₂:MeOH gradient to give6-((6-(3,5-difluorophenyl)-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)-3-methoxyquinoline(72 mg, 17% yield). LRMS (ESI) m/z calcd for C₂₃H₁₄F₅N₄O (M+H) 457.1.found 457.0.

tert-butyl 2-(3-(2-methoxyethoxy)quinolin-6-yl)acetate

A flask was charged with tert-butyl 2-(3-hydroxyquinolin-6-yl)acetate(581.04 mg, 2.241 mmol) and triphenylphosphine (1.175 g, 4.482 mmol)then sealed with a septum and an placed under N₂. Benzene (10 mL) wasadded, followed by 2-methoxyethanol (0.8838 ml, 11.20 mmol). Theheterogeneous solution was cooled to 0° C., and di-tert-butylazodicarboxylate (1.032 g, 4.482 mmol) was added as a solid in a singleportion. The solution was allowed to warm to rt and maintained 20 h. Thesolution was then partitioned between saturated aqueous. NH₄Cl, and thelayers separated. The aqueous layer was extracted with EtOAc (2×50 mL),and the combined organic layers were washed with brine, dried (MgSO₄),and concentrated in vacuo. The resulting residue was purified by MPLC(Teledine Isco combiFlash Companion), 80 g SiO₂, solvent system: 90:10hexanes:EtOAc gradient to 50:50 hexanes:EtOAc to give tert-butyl2-(3-(2-methoxyethoxy)quinolin-6-yl)acetate (585.2 mg, 82% yield). LRMS(ESI) m/z calcd for C₁₈H₂₄NO₄ (M+H) 318.2. found 318.3.

tert-butyl 2-(3-((1,4-dioxan-2-yl)methoxy)quinolin-6-yl)acetate(racemate)

The title compound was assembled from tert-butyl2-(3-hydroxyquinolin-6-yl)acetate and (1,4-dioxan-2-yl)methanolaccording to the procedure described for tert-butyl2-(3-(2-methoxyethoxy)quinolin-6-yl)acetate.

N′-(6-chloropyridazin-3-yl)-2,2-difluoro-2-(3-(2-methoxyethoxy)quinolin-6-yl)acetohydrazide

The title compound was assembled from1-(6-chloropyridazin-3-yl)hydrazine and tert-butyl2-(3-(2-methoxyethoxy)quinolin-6-yl)acetate as described in GeneralMethod I. LRMS (ESI) m/z calcd for C₁₈H₁₇ClF₂N₅O₃ (M+H) 424.1. found424.2.

EXAMPLE 4646-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)difluoromethyl)-3-(2-methoxyethoxy)quinoline

A sealable microwave vial was charged withN′-(6-chloropyridazin-3-yl)-2,2-difluoro-2-(3-(2-methoxyethoxy)quinolin-6-yl)acetohydrazide(46.98 mg, 111 μmol), 1,2-dimethoxyethane (1.5 mL), and 1 drop of conc.HCl. The vial was sealed and heated at 130° C. for 40 min. The solutionwas concentrated and purified by MPLC (Teledine Isco combiFlashCompanion). The residue was taken up in minimal CH₂Cl₂ and absorbed ontoa 5 g loading cartridge and passed through a Redi-Sep® pre-packed silicagel column (12 g) using 98:2 CH₂Cl₂: MeOH to 90:10 CH₂Cl₂:MeOH to afford6-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)difluoromethyl)-3-(2-methoxyethoxy)quinoline(25.3 mg, 56.2% yield) as a colorless solid. LRMS (ESI) m/z calcd forC₁₈H₁₅ClF₂N₅O₂ (M+H) 406.1. found 406.2.

EXAMPLE 4656-((6-(3,5-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)difluoromethyl)-3-(2-methoxyethoxy)quinoline

The title compound was synthesized from6-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)difluoromethyl)-3-(2-methoxyethoxy)quinolineand 3,5-difluorophenylboronic acid in a similar manner as that describedfor6-((6-(3,5-difluorophenyl)-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)-3-methoxyquinoline.LRMS (ESI) m/z calcd for C₂₄H₁₈F₄N₅O₂ (M+H) 484.1. found 484.2.

EXAMPLE 466N-((5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine

1) methyl 2-(5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)acetate. Asealable microwave vial was charged with methyl2-(5-chlorofuro[3,2-b]pyridin-3-yl)acetate (1.30 g, 5.74 mmol),palladium(II) acetate (0.129 g, 0.574 mmol), potassium phosphate (3.66g, 17.2 mmol), 3,5-difluorophenylboronic acid (1.81 g, 11.5 mmol), andX-Phos (0.548 g, 1.15 mmol). The vial was sealed, flushed with N₂, thendioxane (20 mL) and H₂O (2 mL) were added. The solution was sparged withN₂ for 10 min, then heated at 100° C. for 24 h. The mixture was thencooled to rt and concentrated for purification by MPLC (Teledine IscocombiFlash Companion). The crude residue was taken up in minimal CH₂Cl₂and absorbed onto a 25 g loading cartridge and passed through aRedi-Sep® pre-packed silica gel column (120 g) using 98:2 Hexanes:EtOActo 70:30 Hexanes:EtOAc gradient to afford methyl2-(5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)acetate (1.46 g, 83.8%yield) as a colorless amorphous solid. LRMS (ESI) m/z calcd forC₁₆H₁₂F₂NO₃ (M+H) 304.1. found 304.2.

2) 2-(5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)acetic acid. To aflask charged with methyl2-(5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)acetate (1.46 g, 5mmol) was added MeOH (1.5 mL), H₂O (0.5 mL), followed by NaOH (2 mL, 6M, 12 mmol) to generate a yellow solution, which was capped andmaintained at rt for 18 h. The solution was acidified with conc. HCl topH=3 and poured into CH₂Cl₂. The layers were separated and the organiclayer was extracted with CH₂Cl₂ (2×10 mL), followed by EtOAc (2×10 mL).The combined organic extracts were dried over Na₂SO₄ and concentrated invacuo to produce a colorless solid, which was of sufficient purity foruse in the next step.

3) methyl(5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)methylcarbamate. To aflask under N₂ charged with2-(5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)acetic acid (1.033 g,3.57 mmol) was added anhydrous CH₂Cl₂ (40 mL). The heterogeneoussolution was cooled to 0° C. and oxalyl chloride (1.6 mL, 17.8 mmol) wasadded, followed by a catalytic amount of DMF. The solution was warmed tort and maintained for 1 h. The solution was concentrated, then taken upin anhydrous acetone and added to a stirring aqueous solution of sodiumazide (1.62 g, 25.0 mmol, in 10 mL H₂O) at 0° C. to generate ahomogeneous orange solution. After 15 min at 0° C., the mixture wasdiluted further with CH₂Cl₂ and stirred an additional 5 min to give ahomogeneous solution. The solution was then partitioned between H₂O andCH₂Cl₂, and the layers were separated. The aqueous layer was extractedwith CH₂Cl₂ (2×10 mL) and the combined organic layers were dried(Na₂SO₄) and concentrated in vacuo. The residue was transferred to a dryflask, evacuated and flushed with N₂ (5×), and anhydrous CH₂Cl₂ (30 mL)was added. The solution was cooled to −78° C., and boron trichloride(5.4 mL, 5.4 mmol, 1.0 M in CH₂Cl₂) was added dropwise. The cold bathwas removed and the solution was allowed to warm to rt, and maintained48 h. Anhydrous methanol (5 mL) was added and the solution maintained atrt for 3 h at which time it was concentrated for purification by MPLC(Teledine Isco combiFlash Companion). The residue was taken up inminimal CH₂Cl₂ and absorbed onto a 25 g loading cartridge and passedthrough a Redi-Sep® pre-packed silica gel column (80 g) using 99:1CH₂Cl₂:MeOH to 90:10:1 CH₂Cl₂:MeOH:NH₄OH to afford methyl(5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)methylcarbamate (680 mg,60% yield) as a brown amorphous solid. LRMS (ESI) m/z calcd forC₁₆H₁₃F₂N₂O₃ (M+H) 319.1. found 319.2.

4) (5-(3,5-difluorophenyl)furo[3,2-b]pyridine-3-yl)methanamine. To aflask charged with methyl(5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)methylcarbamate (680 mg,2137 μmol) was added MeOH (20 mL), then aqueous NaOH (18 mL, 6 N, 106mmol). The solution was heated at reflux for 60 h. The solution wasconcentrated to remove MeOH, then partitioned between CH₂Cl₂ (30 mL) andNaHCO₃ (10 mL). The layers were separated and the aqueous layer wasextracted with CH₂Cl₂ (1×10 mL), then EtOAc (4×25 mL). The combinedorganic layers were concentrated to give a total of(5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)methanamine (306.6 mg,55% yield) as a brown foam. LRMS (ESI) m/z calcd for C₁₄H₁₁F₂N₂O (M+H)261.1. found 261.2.

5)N-((5-(3,5-difluorophenyl)furo[32-b]pyridin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine.A sealable microwave vial was charged with(5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)methanamine (177.6 mg,682 μmol), 8-chloro-3-methoxy-1,5-naphthyridine (146 mg, 751 μmol), andpotassium phosphate (435 mg, 2047 μmol). A septum was attached and thevial was flushed with N₂, then toluene (5 mL) and H2O (1 mL) were addedand the was solution sparged with N₂ for 5 min. The septum was thenquickly removed and tris(dibenzylideneacetone)dipalladium (0) (15.6 mg,17.1 μmol) and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (42.5 mg,68.2 μmol) were added together as solids. The vial was then sealed andthe resulting purple solution was sparged again for 5 min. The mixturewas then heated at 100° C. for 20 h. The mixture was concentrated invacuo for purification by MPLC (Teledine Isco combiFlash Companion). Thecrude residue was taken up in minimal CH₂Cl₂ and absorbed onto a 25 gloading cartridge and passed through a Redi-Sep® pre-packed silica gelcolumn (80 g) using 98:2 CH₂Cl₂:MeOH to 90:10 CH₂Cl₂:MeOH gradient toafford a tan amorphous solid. This solid was additionally trituratedwith CH₂Cl₂ (2×0.5 mL) to giveN-((5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine(103 mg, 36.1% yield). LRMS (ESI) m/z calcd for C₂₃H₁₇F₂N₄O₂ (M+H)419.1. found 419.2.

EXAMPLE 467N-((5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)methyl)-7-(2-methoxyethoxy)-1,5-naphthyridin-4-amine

The title compound was assembled from(5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)methanamine and8-chloro-3-(2-methoxyethoxy)-1,5-naphthyridine in the manner describedfor7-methoxy-N-((5-(3-methylisoxazol-5-yl)furo[3,2-b]pyridin-3-yl)methyl)-1,5-naphthyridin-4-amine.LRMS (ESI) m/z calcd for C₂₅H₂₁F₂N₄O₃ (M+H) 463.2. found 463.2.

Methyl 2-(5-(3-methylisoxazol-5-yl)furo[3,2-b]pyridin-3-yl)acetate Asealable flask was charged with methyl2-(5-chlorofuro[3,2-b]pyridin-3-yl)acetate, palladium (II) acetate (49.8mg, 222 μmol), X-Phos (211 mg, 443 μmol), and3-methyl-5-(tributylstannyl)isoxazole (1319 mg, 3546 μmol). The flaskwas sealed and dioxane (20 mL) was added. The mixture was sparged withN₂ for 10 min, then heated at 100° C. for 48 h. The mixture was cooledto rt and concentrated for purification by MPLC (Teledine IscocombiFlash Companion). The crude residue was taken up in minimal CH₂Cl₂and absorbed onto a 25 g loading cartridge and passed through aRedi-Sep® pre-packed silica gel column (40 g) using 98:2 CH₂Cl₂:MeOH to90:10 CH₂Cl₂:MeOH to afford methyl2-(5-(3-methylisoxazol-5-yl)furo[3,2-b]pyridin-3-yl)acetate (581 mg,96.3% yield). LRMS (ESI) m/z calcd for C₁₄H₁₃N₂O₄ (M+H) 273.1. found273.3.

MW Mass Ex Structure (M + H) Found Method 468

426 426 I 469

442 442 I 470

396 396 I 471

428 428 I 472

501 501 I 473

512 512 I 474

388 388 J

8-chloro-3-fluoro-1,5-naphthyridine

1)5-((5-fluoropyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione.A 150 mL sealed tube was charged with 2,2-dimethyl-1,3-dioxane-4,6-dione(6.0 g, 41.6 mmol) and trimethyl orthoformate (41.6 mL, 41.6 mmol). Thiswas heated to 100° C., and stirred at this temperature for 2 hours.Reaction then cooled to 30° C. and 5-fluoropyridin-3-amine (4.7 g, 41.6mmol) added portion-wise. Reaction vessel resealed and mixture stirredat 100° C. for 3 hours. LC/MS shows completion. Reaction mixture wascooled to room temperature, diluted with hexane, filtered, and air driedto yield5-((5-fluoropyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione(9.1 g, 82% yield) as a bright yellow solid. MS [M+H]=267.2. Calc'd forC₁₂H, FN₂O₄=266.2.

2) 7-fluoro-1,5-naphthyridin-4(1H)-one. A 500 mL round bottom flaskequipped with a reflux condenser was charged with5-((5-fluoropyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione(8.0 g, 30.0 mmol) and diphenyl ether (83.5 mL). This was heated to 250°C. in heating mantle and allowed to stay at this temperature for fiveminutes. Cooled to room temperature, diluted with hot hexanes, andfiltered to afford 7-fluoro-1,5-naphthyridin-4(1H)-one (2.2 g, 45%yield) as a crude brown solid. The title compound was used withoutfurther purification. MS [M+H]=165.2, Calc'd for C₈H₅FN₂O=164.14.

3) 8-chloro-3-fluoro-1,5-naphthyridine. A pressure resistant vial wascharged with 7-fluoro-1,5-naphthyridin-4(1H)-one (600 mg, 3.66 mmol) andPOCl3 (6.8 mL, 73.1 mmol). Vessel sealed and stirred at 110° C. for 16hrs. Reaction mixture was cooled to room temperature and poured onto icewhile stirring vigorously. While keeping reaction mixture at 0° C., itwas basified to pH˜8 with 6N NaOH. Product extracted withdichloromethane. Organic layer collected, dried over sodium sulfate andconcentrated to afford desired material. This was passed through asilica plug in 1-5% (90:10:1 DCM/MeOH/NH₄OH)/DCM to afford8-chloro-3-fluoro-1,5-naphthyridine (430 mg, 64% yield) as a tan solid.MS [M+H]=182.9. Calc'd for C₈H₄ClFN₂=182.58

7-chloro-3H-imidazo[4,5-b]pyridine

1) 4-azabenzimidazole N-oxide. Hydrogen peroxide (30 wt % solution inwater, 38.0 ml, 372 mmol) was added to a suspension of3H-imidazo[4,5-b]pyridine (4.93 g, 41.4 mmol) in AcOH (40 mL) at roomtemperature. The resulting reaction mixture was stirred at 80° C. for 3h, cooled to RT and concentrated in vacuo to a volume ˜50 mL.Concentration to dryness was done using a stream of N₂. The resultingresidue was suspended in water (˜10 mL). Filtration afforded the titlecompound (4.61 g, 82.4% yield).

2) 7-chloro-3H-imidazo[4,5-b]pyridine. A 50 mL round bottom flask set upwith a reflux condenser under nitrogen atmosphere was charged4-azabenzimidazole N-oxide (1.2 g, 8.88 mmol) and 11 mL of DMF. This washeated to 50° C. and methanesulfonyl chloride (1.86 ml, 23.98 mmol) wasadded dropwise via syringe. The resulting mixture was heated to 80° C.and stirred at this temperature for 16 hours. This was cooled to roomtemperature and quenched with water (approximately 10 mL) and reactionmixture brought to pH 7 by adding 6N NaOH aqueous solution. The reactionwas extracted four times with dichloromethane (50 mL). Some product waspresent in aqueous layer; this was concentrated and residue set aside.The combined organic layers were dried with sodium sulfate, filtered,and concentrated. The material was purified via column chromatography(RediSep 40 g column, gradient elution 0-10% MeOH:DCM) to afford7-chloro-3H-imidazo[4,5-b]pyridine (450 mg, 33.0% yield). MS[M+H]=154.2. Calc'd C₆H₄ClN₃=153.56.

8-chloro-1,5-naphthyridin-3-ol

A pressure-resistant vial was charged with8-chloro-3-methoxy-1,5-naphthyridine (2.5 g, 12.8 mmol), borontribromide (13.4 mL, 141.3 mmol) and dichloroethane (0.6M, 21.4 mL).Vessel sealed and mixture stirred at 60° C. for 16 hrs. Next day thereaction mixture was chilled in ice bath and diluted withdichloromethane (200 mL). This was allowed to sit under nitrogen systemuntil all fuming ceased. The resulting yellow solid material was thenfiltered and dried under high vacuum. This was suspended in 40% (90:10:1DCM/MeOH/NH₄OH)/DCM and purified in this system by ISCO silica gelchromatography (80 g) afford 8-chloro-1,5-naphthyridin-3-ol (1.3 g, 56%yield). MS [M+H]=181.2. Calc'd for C₈H₅ClN₂O=180.59.

3-(2-bromoethoxy)-8-chloro-1,5-naphthyridine

A resealable pressure bottle was charged with8-chloro-1,5-naphthyridin-3-ol (400 mg, 2.2 mmol), 2-dibromoethane (3.2mL, 37.7 mmol), and DMF (0.15M, 14.8 mL). Vessel sealed and placed in apre-heated at 65° C. oil bath. Reaction allowed to stir at thistemperature for 4 hrs. Reaction cooled to room temperature and passedthrough a pad of celite. Filtrate concentrated and purified by ISCOsilica gel chromatography (20-40% EtOAc/Hexanes) to afford3-(2-bromoethoxy)-8-chloro-1,5-naphthyridine (460 mg, 72% yield). MS[M+H]=289.0 Calc'd for C₁₀H₈BrClN₂O=287.54

The following compound was prepared using the procedure for3-(2-bromoethoxy)-8-chloro-1,5-naphthyridine:

-   8-chloro-3-((tetrahydrofuran-2-yl)methoxy)-1,5-naphthyridine;-   8-chloro-3-((tetrahydrothiophen-1,1-dioxide-3-yl)methoxy)-1,5-naphthyridine    (starting with the alkyl chloride).

(R)-8-chloro-3-(2-(3-fluoropyrrolidin-1-yl)ethoxy)-1,5-naphthyridine

A 25 mL round bottom flask at rt was charged with(R)-3-fluoropyrrolidine hydrochloride (124 mg, 0.99 mmol). To this wasadded potassium carbonate (365 mg, 2.64 mmol),3-(2-bromoethoxy)-8-chloro-1,5-naphthyridine (190 mg, 0.66 mmol), sodiumiodide (149 mg, 0.99 mmol) and DMF (2 mL). Reaction mixture placed inoil bath preheated to 60° C. and allowed to stir for 16 hrs. Reactionmixture passed through celite cake, rinsed with 10% MeOH/DCM andfiltrate concentrated to afford yellow oil. This was purified by ISCOsilica gel chromatography (20-40% EtOAC/Hexanes) to afford(R)-8-chloro-3-(2-(3-fluoropyrrolidin-1-yl)ethoxy)-1,5-naphthyridine(105 mg, 54% yield). MS [M+H]=296.2. Calc'd for C₁₄H₁₅ClFN₃O=295.7.

The following compounds were prepared in a similar fashion as8-chloro-3-(2-(3-fluoropyrrolidin-1-yl)ethoxy)-1,5-naphthyridine:

-   8-chloro-3-(2-(3-fluoropyrrolidin-1-yl)ethoxy)-1,5-naphthyridine;-   8-chloro-3-(2-(3,3-difluoropyrrolidin-1-yl)ethoxy)-1,5-naphthyridine;-   1-(2-(8-chloro-1,5-naphthyridin-3-yloxy)ethyl)pyrrolidin-3-ol;-   3-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-8-chloro-1,5-naphthyridine    (using NaH as the base);-   3-(2-(1H-pyrazol-1-yl)ethoxy)-8-chloro-1,5-naphthyridine;-   3-(2-(1H-1,2,3-triazol-1-yl)ethoxy)-8-chloro-1,5-naphthyridine.

8-chloro-3-(2,2,2-trifluoroethoxy)-1,5-naphthyridine

A resealable pressure bottle was charged with8-chloro-1,5-naphthyridin-3-ol (80 mg, 0.44 mmol), cesium carbonate (433mg, 1.3 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (360 mg,1.55 mmol), and DMF (0.9 ml). Vessel sealed and placed in a pre-heatedat 50° C. oil bath. Reaction allowed to stir at this temperature for 45minutes. LC/MS shows complete conversion. Quench with water, dilute withaqueous sodium bicarbonate solution and dichloromethane. Layersseparated, organic layer collected and dried over sodium sulfate. Thiswas concentrated to afford yellow oil; which was purified by ISCO silicagel chromatography (20-40% EtOAc/Hexanes) to afford8-chloro-3-(2,2,2-trifluoroethoxy)-1,5-naphthyridine (65 mg, 56% yield).MS [M+H]=263.0@1.89 minutes. Calc'd for C₁₀H₆ClF₃N₂O=262.6.

8-chloro-3-(2,2-difluoroethoxy)-1,5-naphthyridine

The title compound was prepared using the method described for8-chloro-3-(2,2,2-trifluoroethoxy)-1,5-naphthyridine.

8-chloro-3-(2-methoxyethoxy)-1,5-naphthyridine

A round bottom flask under nitrogen environment was charged with8-chloro-1,5-naphthyridin-3-ol (1.05 g, 5.8 mmol), 22.8 g ofPS-Triphenylphosphine (loading: 2.2 mmol/g), 2-methoxyethanol (2.2 mL,27.9 mmol), and THF (29.1 ml, 5814 μmol)/DCM (58.1 mL). Mixture cooledto 0° C. and to this was added DEAD (1.84 mL) dropwise via syringe.Reaction mixture allowed to stir at room temperature for 16 hours.Diluted with 50 mL of 10% MeOH/dichloromethane and resin bound reagentfiltered. Filtrate concentrated under reduced pressure and purified byISCO silica gel chromatography (10-30% EtOAc/Hexanes) to afford8-chloro-3-(2-methoxyethoxy)-1,5-naphthyridine (770 mg, 55% yield) aswhite solid. MS [M+H]=238.9. Calc'd for C₁₁H₁₁ClN₂O₂=238.67.

The following compounds were prepared in a similar fashion as8-chloro-3-(2-methoxyethoxy)-1,5-naphthyridine:

-   8-chloro-3-(2-(pyrrolidin-1-yl)ethoxy)-1,5-naphthyridine;-   8-chloro-3-(3-morpholinopropoxy)-1,5-naphthyridine;-   3-((1,4-dioxan-2-yl)methoxy)-8-chloro-1,5-naphthyridine;-   8-chloro-3-(pyrrolidin-2-ylmethoxy)-1,5-naphthyridine.

8-chloro-3-(difluoromethoxy)-1,5-naphthyridine

A round bottom flask under nitrogen atmosphere was charged with sodium2-chloro-2,2-difluoroacetate (0.49 g, 3.2 mmol),8-chloro-1,5-naphthyridin-3-ol (0.25 g, 1.4 mmol), cesium carbonate (1.4g, 4.2 mmol), and DMF (2.8 mL, 0.5M). This was then placed in a 100° C.preheated oil bath and stirred at this temperature for 3 hours. Reactionmixture diluted with 10% Methanol/Dichloromethane and filtered overcelite. Filtrate concentrated and purified by ISCO silica gelchromatography (40 g) in 1% MeOH/DCM to afford pure8-chloro-3-(difluoromethoxy)-1,5-naphthyridine (0.18 g, 56% yield) aswhite solid. MS [M+H]=231.2. Calc'd for C₉H₅ClF₂N₂O=230.60.

8-chloro-3-((2-methyl-2H-1,2,4-triazol-3-yl)methoxy)-1,5-naphthyridine

1) 2-methyl-2H-1,2,4-triazole-3-carbaldehyde. A dry round bottom flaskunder nitrogen atmosphere was charged with 1-methyl-1H-1,2,4-triazole(1.0 g, 12.04 mmol) and THF (6.0 ml, 2M). This was cooled to 0° C.followed by addition of 2M solution of isopropylmagnesium chloride inTHF (6.6 mL, 13.24 mmol) via syringe. Ice bath removed and reactionallowed to stir at room temperature for 1.5 hours. Reaction mixturecooled back to 0° C. and N,N-dimethylformamide (1.39 ml, 18.05 mmol)added dropwise via syringe. Reaction mixture allowed to warm up to roomtemperature over 1 hour and stirred at this temperature for 16 hours.Next day reaction mixture was quenched with 2N HCl and mixture dilutedwith dichloromethane. Layers separated, and aqueous layer neutralizedwith aq. sodium bicarbonate solution and extracted with dichloromethane.All organic layers combined, dried over sodium sulfate and concentratedat room temperature (most THF remains) to afford clear material. Thiswas purified by ISCO silica gel chromatography (10-40% EtOAc/Hex) toafford 2-methyl-2H-1,2,4-triazole-3-carbaldehyde (1.0 g, 75% yield).Yield was estimated based on H′NMR. Product was isolated as a solutionin EtOAc (did not remove all EtOAc due to volatility of aldehyde,b.p.˜60° C.). MS [M+H]=112.2; MS [M+H+ H₂O]=130.2@0.23 minutes. Calc'dfor C₄H₅N₃O=111.10.

2) (2-methyl-2H-1,2,4-triazol-3-yl)methanol.2-methyl-2H-1,2,4-triazole-3-carbaldehyde (0.50 g, 4.50 mmol) in MeOH(10 mL) was treated with sodium borohydride (0.17 g, 4.50 mmol) at roomtemperature and allowed to stir for 2 hours. Reaction mixture wasquenched with aqueous sodium bicarbonate solution, diluted with 10%MeOH/DCM, and organic layer collected. Aqueous layer was saturated withsodium sulfate and extracted with 50 mL of dichloromethane (3 times).Organic portions combined, dried over sodium sulfate and concentrated to¼ volume at room temp. This was then diluted with ether, causing aprecipitate to form. This was concentrated yielding2-methyl-2H-1,2,4-triazol-3-yl)methanol as a foamy white solid (0.44 g,86.4% yield). This was used ‘as is’ for next step. MS [M+H]=114.2.Calc'd for C₄H₇N₃O=113.1.

3)8-chloro-3-((2-methyl-2H-1,2,4-triazol-3-yl)methoxy)-15-naphthyridine.The title compound was prepared in a similar fashion as8-chloro-3-(2-methoxyethoxy)-1,5-naphthyridine.

3-bromo-8-chloro-1,5-naphthyridine

1)5-((5-bromopyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione.A 350 mL sealed tube was charged with 2,2-dimethyl-1,3-dioxane-4,6-dione(21.6 g, 150.0 mmol) and triethyl orthoformate (150 mL, 150.0 mmol).This was heated to 100° C., and stirred at this temperature for 2 hours.Reaction then cooled to 30° C. and 55-bromopyridin-3-amine (25.95 g,150.0 mmol) added portion-wise. Reaction vessel resealed and mixturestirred at 100° C. for 3 hours. LC/MS shows completion. Reaction mixturewas cooled to room temperature, diluted with hexane, filtered, and airdried to yield5-((5-bromopyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione(41.5 g, 85% yield) as a yellow solid. MS [M+H]=327.0. Calc'd forC₁₂H₁₁BrN₂O₄=327.1.

2) 7-bromo-1,5-naphthyridin-4(1H)-one. A 500 mL round bottom flaskequipped with a reflux condenser was charged with5-((5-bromopyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione(10.5 g, 32.1 mmol) and diphenyl ether (84.5 mL, 32.1 mmol). This washeated to 250° C. in heating mantle and allowed to stay at thistemperature for 1 hour. Reaction mixture was cooled to room temperatureand diluted with 300 mL of Hexanes. This was heated to 60° C. andtriturated in this system for 3 hrs to afford7-bromo-1,5-naphthyridin-4(1H)-one (6.05 g, 84% yield) as a crude brownsolid. This was used without further purification. MS[M+H]=227.0. Calc'dfor C₈H₅BrN₂O=225.0.

3) 3-bromo-8-chloro-1,5-naphthyridine.7-bromo-1,5-naphthyridin-4(1H)-one (23.8 g, 105.8 mmol), acetonitriel(192 mL, 105.8 mmol), and DMF (2.05 mL, 26.5 mmol) were placed in a3-necked round bottom flask set up with a reflux condenser. Argonbubbled through. Reaction mixture brought to reflux (˜95° C.). Oxalylchloride (28.7 ml, 328.1 mmol) was added dropwise via addition funnelover 40 minutes and reaction allowed to stir at this temperature for 16hrs. Reaction mixture cooled to 0° C. and basified to pH ˜8 with aqueoussodium bicarbonate solution. Product extracted with DCM (500 mL) threetimes. Organic layers combined, dried over sodium sulfate andconcentrated to afford brown solid. This was purified by ISCO silica gelchromatography to afford 3-bromo-8-chloro-1,5-naphthyridine (3.6 g, 14%yield) as fluffy tan solid.

MS[M+H]=245.0@. Calc'd for C₈H₄BrClN₂=243.5.

8-chloro-N-(diphenylmethylene)-1,5-naphthyridin-3-amine

A 25 ml round bottom flask set up under nitrogen was charged withPd₂(dba)₃ (301 mg, 0.33 mmol), BINAP (614 mg, 0.99 mmol) and sodiumtert-butoxide (237 mg, 2.46 mmol). System was purged with Argon and3-bromo-8-chloro-1,5-naphthyridine (400 mg, 1.64 mmol),diphenylmethanimine (0.28 mL, 1.64 mmol), and toluene (1M, 1.64 mL) wereadded. This was placed in a preheated oil bath at 80° C. and stirred atthis temperature for 16 hours. Reaction cooled to room temperature,diluted with dichloromethane, and passed over a celite cake. Filtratecollected was concentrated to afford brown oil. This was purified byISCO silica gel chromatography (40 g, 1% MeOH/DCM over 50 mins) toafford clean 8-chloro-N-(diphenylmethylene)-1,5-naphthyridin-3-amine(280 mg, 50% yield). MS[M+H]=344.0. Calc'd for C₂₁H₁₄ClN₃=343.8.

8-chloro-N-(2-methoxyethyl)-1,5-naphthyridin-3-amine

1) 8-chloro-1,5-naphtpyridin-3-amine. A round bottom flask undernitrogen was charged with8-chloro-N-(diphenylmethylene)-1,5-naphthyridin-3-amine (315 mg, 0.92mmol), 2M aqueous HCl (1.42 mL, 2.84 mmol), and tetrahydrofuran (0.25M,3.67 mL). This was stirred at RT for 30 minutes. Reaction basified withaq. sodium bicarbonate solution and product extracted withdichloromethane. This was dried over sodium sulfate and concentrated toafford orange solid; which was purified via ISCO silica gelchromatography, 40 g column, 30% (90/10/1 DCM:MeOH:NH₄OH)/DCM over 40minutes to afford 7-amino-1,5-naphthyridin-4-ol (140 mg, 95% yield) asyellow solid. MS[M+H]=180.2. Calc'd for C₈H₆ClN₃=179.6.

2) 8-chloro-N-(2-methoxyethyl)-1,5-naphthyridin-3-amine. A round bottomflask under nitrogen atmosphere was charged with8-chloro-1,5-naphthyridin-3-amine (160 mg, 0.89 mmol), DMF (2.2 mL, 0.89mmol). This was cooled to 0° C. and SODIUM HYDRIDE (60% dispersion inoil) (107 mg, 4.45 mmol) added portionwise. This was quickly followed byaddition of 1-bromo-2-methoxyethane (0.12 mL, 1.25 mmol) dropwise viasyringe. Ice bath removed and reaction mixture heated to 85° C. andstirred at this temperature for 16 hours. Reaction diluted with 5 mL of5% MeOH/Dichloromethane, loaded onto silica gel column and eluted with2% MeOH/DCM to afford8-chloro-N-(2-methoxyethyl)-1,5-naphthyridin-3-amine (70 mg, 33% yield)as a light yellow solid. MS[M+H]=238.2. Calc'd for C₁₁H₁₂ClN₃O=237.7.

N-(8-chloro-1,5-naphthyridin-3-yl)-2-methoxyacetamide

A round bottom flask under nitrogen was charged with8-chloro-1,5-naphthyridin-3-amine (41 mg, 0.23 mmol), triethylamine (64μl, 0.46 mmol), and dichloromethane (1 mL). To this was added2-methoxyacetyl chloride (42 μL, 0.46 mmol) dropwise via syringe andreaction allowed to stir overnight at room temperature. Next dayreaction mixture was diluted with dichloromethane and washed withaqueous sodium bicarbonate solution. Layers separated and organic layerdried over sodium sulfate to afford yellow oil. This was purified byISCO silica gel chromatography (2-5% MeOH/DCM) to affordN-(8-chloro-1,5-naphthyridin-3-yl)-2-methoxyacetamide (43 mg, 75% yield)as light yellow solid. MS[M+H]=251.9. Calc'd for C₁₁H₁₀ClN₃O₂=251.7.

8-chloro-3-morpholino-1,5-naphthyridine

A round bottom flask under nitrogen atmosphere was charged withPd₂(dba)₃ (578 mg, 0.63 mmol), Xantphos (1.1 g, 1.89 mmol), and sodiumtert-butoxide (364 mg, 3.79 mmol). This was purged with Argon followedby addition of 3-bromo-8-chloro-1,5-naphthyridine (615 mg, 2.53 mmol),morpholine (0.22 mL, 2.53 mmol), and toluene (1M, 2.53 mL). This wasthen placed in a preheated oil bath at 80° C. After 2.5 hours, reactionwas stopped, cooled to room temp and diluted with Dichloromethane. Thiswas passed over a celite cake and filtrate concentrated to afford brownoil; which was purified by ISCO silica gel chromatography (40 g, 1%MeOH/DCM over 50 mins) to afford 8-chloro-3-morpholino-1,5-naphthyridine(200 mg, 32% yield). MS[M+H]=250.2. Calc'd for C₁₂H₁₂ClN₃O=249.7.

4-bromo-1-phenyl-1H-pyrazole

A sealable tube was charged with 4-bromopyrazole (4.000 g, 27.2 mmol),1-iodobenzene (3.64 ml, 32.7 mmol), (+/−)-trans-1,2-diaminocyclohexane(0.654 ml, 5.44 mmol), Copper iodide (I) (0.518 g, 2.72 mmol), potassiumcarbonate (8.28 g, 59.9 mmol) and 13 mL dioxane added. The mixture wasblanketed with N2, the vessel sealed and heated to 100 C for 16 h. Themixture was allowed to cool to rt, diluted with EtOAc, washed withwater, and an emullsion formed. The organic layer separated and theaqueous emulsion mixture was filter through a pad of celite and rinsedwith EtOAc, and sat. NaHCO₃. The combined organic layers were dried overNa₂SO₄, filtered and evaporate. The mixture was purified via flashchromatography using a 0% to 100% CH₂Cl₂ in hexanes gradient. The titlecompound was collected as a yellow solid (3.18 g)

1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared in the same manner as1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolestarting with 4-bromo-1-phenyl-1H-pyrazole.

4-bromo-1-(tetrahydrofuran-3-yl)-1H-pyrazole

The title compound was prepared in the same manner as4-bromo-1-(cyclobutyl)-1H-pyrazole, but using tetrahydrofuran-3-ylmethanesulfonate (prepared according to procedures known in the art).

1-(tetrahydrofuran-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared in the same manner as1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolestarting with 4-bromo-1-(tetrahydrofuran-3-yl)-1H-pyrazole.

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-cyclopropyl-1H-pyrazole

a) 1-cyclopropyl-1H-pyrazole. In a 1000 mL 3-neck flask, to a mixture ofpotassium hydroxide (104 g, 1857 mmol) in water (200 mL) was addedcyclopropylamine (131 ml, 1857 mmol) and the mixture stirred at 50 C. Asolution of hydroxylamine-O-sulfonic acid (HOS)(30.00 g, 265 mmol) in100 mL water was added dropwise resulting in the formation of a whiteprecipitate after the first few drops. The stirring stopped during thefirst half of the addition and some cyclopropylamine condensed on top ofthe HOS soln. Additional amine (10 mL) was added to the reaction andaddition of HOS solution continued. Mixture bubbles during the addition.The flask was remove from heat and cool in ice bath to 25 C. HCl (conc)was added slowly, 150-200 mL, to achieve PH 3. The mixture was filteredto remove the white solid and the filtrate heated with1,1,3,3-tetramethoxypropane (43.7 ml, 265 mmol). The mixture took 1.5 hto reach 90 C, maintained the temperature at 90 for 1 h, then allowedthe mixture to cool to 40 C with stirring for an additional 17 h. Themixture was allowed to cool to ˜35 C and extracted with Et₂O (400 mLthen 2×100 mL), the combined organic layers were with water, 6N NaOH, 2NNaOH, then sat NaHCO₃, and the organic layer dried over Na₂SO₄, filteredand evaporate gently. Upon evaporation, when volume is reduced from ˜600mL to ˜100 mL, the white solid that has precipitated was filtered. Thetitle compound was obtained as a golden liquid (˜2 g).

b) 4-bromo-1-cyclopropyl-1H-pyrazole. To a golden solution of1-cyclopropyl-1H-pyrazole (2.360 g, 22 mmol) in 100 mL chloroform, wasadded bromine (1.2 ml, 24 mmol) as a soln in 100 mL CHCl₃ dropwise over1.5 h. the mixture was heated in oil bath to 60 C for 2 h. The mixturewas allowed to cool to RT, washed with sat NaHCO₃, dried over Na₂SO₄,filtered and evaporated to afford the title compound as a tan liquid(3.64 g).

c)4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-cyclopropyl-1H-pyrazoleThe title compound was prepared in the same manner as1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolestarting with 4-bromo-1-cyclopropyl-1H-pyrazole.

tert-butyl(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate

A 2-L round bottom flask equipped with a magnetic stirbar was chargedwith di(1H-imidazol-1-yl)methanone (121 g, 749 mmol) and acetonitrile(500 mL). The stirred slurry was cooled by immersing the flask in an icebath. A solution of N-Boc glycine (125 g, 714 mmol) in acetonitrile (500mL) was added via a 500-mL addition funnel over the course of 30-45 min.The mixture was aged for 1 h while a 5-L, 3-neck, round bottomflaskequipped with a mechanical overhead stirrer and a thermocouple w/adapterwas charged with 1-(6-chloropyridazin-3-yl)hydrazine (108 g, 749 mmol)and acetonitrile (900 mL) and cooled to <5 deg C. in an ice bath. Thecold solution of the acylimidazole was then transferred via apolyethylene cannula into the thick suspension of the hydrazine over aperiod of 30-45 min). The ice bath was removed, and the mixture wasallowed to warm. After 2.5 h of stirring, 4-methylbenzenesulfonic acidhydrate (143 g, 749 mmol) was added. The flask was then equipped with aheating mantle and a reflux condenser and was heated to reflux (82 degC.) for 13 h, then cooled back to about 60 deg C. At this point, thewarm solution was vacuum filtered through paper. The brown filtrate wasthen concentrated by rotary evaporation. The resulting thickyellow-brown slurry was stirred in an ice bath and diluted with ACN(about 100 mL). After stirring for 1 h, the solids were isolated byvacuum filtration, washed with ice-cold 1:1 ACN/H₂O (2×150 mL) andair-dried on the filter until a freely flowing solid was obtained (159g, 78.5% yield).

EXAMPLE 4756-(Difluoro(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)quinoline

To a stirring suspension of1-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)hydrazine (190 mg,917 μmol), methyl 2,2-difluoro-2-(quinolin-6-yl)acetate (218 mg, 917μmol), triphenylphosphine polymer supported (241 mg, 917 μmol), DIEA(200 μl, 1146 μmol) in DCM (4 mL) was added 2,2,2-trichloroacetonitrile(92 μl, 917 μmol). The reaction vessel was then appropriately sealed andheated to 150° C. with microwaves for 15 min. The reaction was thenconcentrated onto dry silica under reduced pressure and product purifiedon silica (40 g) eluting with 1-4% of 2 M NH₃ in MeOH/DCM. The productwas then further purified by RP-HPLC eluting with water/ACN (0.1% TFA).Collected fractions concentrated under reduced pressure, dissolved inMeOH/DCM (5 mL) and stirred with Si-Carbonated (300 mg; 0.2 mmol) for 30min at 23° C. Solids were then removed by filtration, and washed withMeOH (3×1 mL). The filtrate was then concentrated under reducedpressure, and product isolated as an off white solid. MS (ESI pos. ion)m/z: 395 (MH+). Calc'd exact mass for C₂₀H₁₃F₃N₆: 394.

2,2-Difluoro-2-(Quinolin-6-yl)acetohydrazide

A solution methyl 2,2-difluoro-2-(quinolin-6-yl)acetate (400 mg, 1686μmol) and anhydrous hydrazine (2153 μl, 67453 μmol) in MeOH (4 mL) wasstirred for 1 h at 23° C. The solvents were then removed under reducedpressure to provide product as a white solid. MS (ESI pos. ion) m/z: 238(MH+). Calc'd exact mass for C₁₁H₉F₂N₃O: 237.

EXAMPLE 4766-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)difluoromethyl)quinoline

A suspension of 2,2-difluoro-2-(quinolin-6-yl)acetohydrazide (2000 mg,8432 μmol) and 3,6-dichloropyridazine (3768 mg, 25295 μmol) in 1.25 MHCl in MeOH (20 mL) was heated to 90° C. with microwaves for 50 min. Thesolvents were then removed under reduced pressure and residuepartitioned between 9:1 CHCl₃/IPA (60 mL) and 1 M NaOH (20 mL). Theorganic phase then dried over MgSO₄, concentrated, then purified onsilica (120 g) eluting with 1>2.5% of 2 M NH₃ in MeOH/DCM to provideproduct isolated as a dark tan soild. MS (ESI pos. ion) m/z: 332 (MH+).Calc'd exact mass for C₁₅H₈ClF₂N₅: 331.

Mass Ex Structure MW Found Method 477

407 408 L 478

427 428 L 479

391 392 L 480

407 408 L 481

371 372 M 482

408 409 M 483

403 404 M

tert-Butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethylcarbamate

A suspension of tert-butyl 4-bromophenethylcarbamate (2700 mg, 8994μmol), bis(pinacolato)diboron (2284 mg, 8994 Smol),bis(pinacolato)diboron (2284 mg, 8994 μmol), potassium acetate (1765 mg,17989 μmol) in dioxane (12 mL) was sparged with argon for 5 min thenheated to 120° C. in an appropriately sealed vessel for 1 h. Thereaction was then partitioned between ether (50 mL) and 5% NaHCO₃ (25mL). The organic phase was then dried over MgSO₄, concentrated, thenpurified on silica (120 g) eluting with 10>30% EtOAc/Hexanes. Theproduct tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethylcarbamate (2200mg, 70% yield) was isolated as a white solid. MS (ESI pos. ion) m/z: 292(MH+1−56). Calc'd exact mass for C₁₉H₃₀BNO₄: 347.

EXAMPLE 4842-(4-(3-(Difluoro(quinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)ethanamine

a) tert-Butyl2-(4-(3-(difluoro(quinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)ethylcarbamate.A suspension of6-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)difluoromethyl)quinoline(350 mg, 1055 μmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethylcarbamate (733mg, 2110 μmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(ii)dichloride dichloromethanecomplex (77 mg, 106 μmol), Na2CO3 (447 mg, 4221 μmol) in DME (4 mL) andwater (2 mL) was sparged with argon for 5-min then heated to 85° C. inan appropriately sealed vessel for 4 h. The reaction was thenpartitioned between DCM (30 mL) and 1 M NaOH (10 mL). The organic phasewas then dried over MgSO₄, concentrated, then purified on silica (40 g)eluting with 1>4% of 2 M NH₃ in MeOH/DCM. The product was isolated as anoff white solid.

b)2-(4-(3-(Difluoro(quinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)ethanamine.A solution of tert-butyl2-(4-(3-(difluoro(quinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)ethylcarbamate(70 mg, 136 μmol) in DCM (1 mL) and TFA (1 mL) was stirred for 30 min at23° C. The solvents were then removed under reduced pressure and crudeproduct purified by RP-HPLC eluting with water/ACN (0.1% TFA). Thedesired collected fractions were then concentrated under reducedpressure and the resulting residue dissolved in MeOH/DCM (5 mL).Solution was then stirred as a suspension with Si-Carbonated (300 mg;0.2 mmol) for 30 min at 23° C. The solids were then removed byfiltration, washed with MeOH (3×1 mL), and filtrate concentrated underreduced pressure. The product was isolated as a white fluffy solid. MS(ESI pos. ion) m/z: 417 (MH+). Calc'd exact mass for C₂₃H₁₈F₂N₆: 416.

N′-(6-chloropyridazin-3-yl)-2-(quinolin-6-yl)propanehydrazide

To a stirring solution of 2-(quinolin-6-yl)propanoic acid (3260 mg,16201 μmol) and DIEA (2830 μl, 16201 μmol) in DMF (25 mL) was addedo-(7-azabenzotriazol-1-yl)-n,n,n′,n-tetramethyl uroniumhexafluorophosphate (6160 mg, 16201 μmol) whole at 23° C. undernitrogen. The solution was stirred for 60 min, cooled to 0° C., thenadded 1-(6-chloropyridazin-3-yl)hydrazine (2342 mg, 16201 μmol). After20 h stirring at 23° C., the reaction was then partitioned between 9:1CHCl₃/IPA (100 mL) and 5% NaHCO₃ (50 mL). The organic phase was thendried over MgSO₄, concentrated to an oil, then purified on silica (120g) eluting with 0>10% of 2 M NH₃ in MeOH/DCM. The product was isolatedas an off white solid. MS (ESI pos. ion) m/z: 328 (MH+). Calc'd exactmass for C₁₆H₁₄ClN₅O: 327.

6-(1-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline

A solution ofN′-(6-chloropyridazin-3-yl)-2-(quinolin-6-yl)propanehydrazide (2700 mg,8238 μmol) in TFA (20 mL) was heated to 120° C. with microwaves (2 bar;10 watts) for 40 min. The solution was concentrated under reducedpressure then partitioned between 9:1 CHCl₃/IPA (75 mL) and 1 M NaOH(100 mL). The aqueous layer was further extracted with 9:1 CHCl₃/IPA(2×20 mL). The combined organics were dried over MgSO₄ then concentratedto an amber oil under reduced pressure. The product was isolated as offwhite crystalline solid from ACN. MS (ESI pos. ion) m/z: 310 (MH+).Calc'd exact mass for C₁₆H₁₂ClN₅: 309. Enantiomer resolved with:Chiralpak AD-H (3×25 cm) column using 45% ethanol (0.1% DEA)/CO₂

The following compounds were prepared using same method as tert-Butyl2-(4-(3-(difluoro(quinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)ethylcarbamateand resolved from racemic mixtures:

Mass Ex Structure MW Found Peak # 485

355 356 1 486

355 356 2 487

385 386 1 488

385 386 2 489

372 373 1 490

372 373 2

EXAMPLE 4916-(difluoro(6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline

A suspension of 1-(6-(3-methylisoxazol-5-yl)pyridazin-3-yl)hydrazinehydrochloride (200 mg, 879 μmol) and methyl2,2-difluoro-2-(quinolin-6-yl)acetate (208 mg, 879 μmol) in 5 M HCl (1mL) was appropriately sealed and heated to 150° C. with microwaves for 4h. The reaction was then quenched by a dropwise into cold 5 M NaOH (2mL) and aqueous extracted with CHCl₃/IPA (25 mL). The organic phase wasthen dried over MgSO₄, concentrated, and purified with silica (40 g)eluting with 1>5% 2 M NH₃ in MeOH/DCM. The product was then furtherpurified on RP-HPLC eluting with water/ACN (0.1% TFA). Combinedfractions concentrated, dissolved in DCM (5 mL) and MeOH (5 mL), thenstirred with Si-Carbonate (0.5 g; 35 mmol) for 1 h. Si-Carbonate removedby filtration and filtrated concentrated with <0.5 mL remaining withproduct isolated by trituration. MS (ESI pos. ion) m/z: 379 (MH+).Calc'd exact mass for C₁₉H₁₂F₂N₆O: 378.

3-chloro-6-(3-methylisothiazol-5-yl)pyridazine

To a solution of 5-bromo-3-methylisothiazole (2.42 g, 14 mmol) in 20 mLof THF at −45° C. was added isopropylmagnesium chloride (19 ml, 19 mmol)in THF (1 M). After 20 minutes, zinc(II) chloride (41 ml, 20 mmol) inTHF (0.5 M) was added and the solution was warmed up to rt.3,6-dichloropyridazine (2.4 g, 16 mmol), 3,6-dichloropyridazine (2.4 g,16 mmol) and Q-Phos (2.5 g) were added and the reaction was heated to50° C. for 16 hours. The reaction was then cooled to 23° C. and quenchedwith 60 mL of satd. NH₄Cl aq. solution. The mixture was mixed withcelite and 100 mL of EtOAc. The insoluble material was removed byfiltration. The filtrate was diluted with 40 mL of EtOAc and 30 mL ofwater. The organic phase was separated and washed with 60 mL of brine,dried over Na₂SO₄ and concentrated in vacuo. The residue was purified bya silica gel column chromatography (10% to 80% hex/EtOAc) to afford redsolid as desired product. MS (ESI pos. ion) m/z: 212 (MH+). Calc'd exactmass for C₈H₆ClN₃S: 211.

1-(6-(3-methylisothiazol-5-yl)pyridazin-3-yl)hydrazine

A mixture of 3-chloro-6-(3-methylisothiazol-5-yl)pyridazine (0.85 g, 4.0mmol) and anhydrous hydrazine (3.8 ml, 120 mmol) in 30 mL of sec-BuOHwas heated at 130° C. for 3 hours. The mixture was cooled to 23° C. anddiluted with 5 mL of water. The solid was collected by filtration andwas washed by 2 mL of water to produce a yellow solid. MS (ESI pos. ion)m/z: 208 (MH+). Calc'd exact mass for C₈H₆ClN₃S: 207.

EXAMPLE 4926-(difluoro(6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline

A mixture of methyl 2,2-difluoro-2-(quinolin-6-yl)acetate (0.50 g, 2.1mmol), 1-(6-(3-methylisothiazol-5-yl)pyridazin-3-yl)hydrazine (0.25 g,1.2 mmol) and p-toluenesulfonic acid monohydrate (0.40 g, 2.1 mmol) in 5mL of dioxane was heated at 150° C. for 1 hour in a microwave. Themixture was then diluted with 70 mL of EtOAc and 40 mL of satd. NaHCO₃solution. The organic phase was separated and washed with 40 mL ofbrine, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by a silica gel column chromatography (EtOAc to 10% MeOH/EtOAc)to give yellow glass. The product was further purified by a prep-HPLC togive yellow glass. MS (ESI pos. ion) m/z: 395 (MH+). Calc'd exact massfor C₁₉H₁₂F₂N₆S: 394.

EXAMPLE 4936-(1-(6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline

To a solution of 5-bromo-3-methylisothiazole (1.00 g, 5.6 mmol) in 10 mLof THF at −45° C. (CH₃CN/dry ice) was added isopropylmagnesium chlorideLiCl complex (7.9 ml, 7.9 mmol) (LiCl complex, 1 M in THF). The mixturewas stirred at −45° C. for 20 minutes and to this was added zincchloride, 0.5 M in THF (17 ml, 8.4 mmol) slowly via a syringe. Themixture was then warmed up to rt and continued to stir for additional 30minutes.6-(1-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline(0.5787 g, 1.9 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.51 g,0.56 mmol) and Q-Phos (0.65 g) in 15 mL of N,N-dimethyl acetamide wasadded to the reaction mixture. The reaction was warmed up to 50° C. for6 hours and was quenched with 50 mL of satd. NH₄Cl aq. solution. Themixture was extracted with 150 mL of EtOAc and the organic phase waswashed with 60 mL of brine. The aqueous phases were further extractedwith 100 mL EtOAc. The combined organics were dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by a silica gel columnchromatography (EtOAc to 15% MeOH in EtOAc) to give afford a red solid.MS (ESI pos. ion) m/z: 373 (MH+). Calc'd exact mass for C₂₀H₁₆N₆S: 372.

EXAMPLE 4943-methyl-6-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoxalin-2(1H)-one

(See Example 495)

EXAMPLE 4953-methyl-7-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoxalin-2(1H)-one

A mixture of tert-butyl2-(2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)acetate (0.10 g, 0.36mmol), tert-butyl 2-(3-methyl-2-oxo-1,2-dihydroquinoxalin-6-yl)acetate(0.10 g, 0.36 mmol), 1(6-phenylpyridazin-3-yl)hydrazine (0.081 g, 0.44mmol) and p-toluenesulfonic acid monohydrate (0.069 g, 0.36 mmol) in 3mL of dioxane was heated with microwave at 150° C. for 1 hour. Themixture was diluted with 70 mL of EtOAc and 40 mL of satd. NaHCO₃solution. The organic phase was separated and was washed with 40 mL ofbrine, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by prep-HPLC to resolve the regiostereomers as examplecompounds 494 and 495. For each regiosteroemer MS (ESI pos. ion) m/z:369 (MH+). Calc'd exact mass for C₂₁H₁₆N₆O: 368.

tert-butyl 2-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)acetate

To a solution of 6-bromo-3-methylquinazolin-4(3H)-one (0.485 g, 2.0mmol), tris(dibenzylideneacetone)dipalladium (0) (0.19 g, 0.20 mmol) andQ-phos (0.20 g) in 40 mL of THF was added 2-tert-butoxy-2-oxoethylzincchloride 0.5 M in diethyl ether (8.1 ml, 4.1 mmol). The reaction washeated at 50° C. for 16 hours and was quenched with 40 mL of satd.NH₄Cl. The mixture was diluted with 60 mL of EtOAc. The organic phasewas separated, washed with brine, dried over Na₂SO₄ and concentrated invacuo to give red solid. The residue was purified by a silica gel columnchromatography (5% EtOAc/Hex to EtOAC) to provide a red solid. MS (ESIpos. ion) m/z: 275 (MH+). Calc'd exact mass for C₁₅H₁₈N₂O₃: 274.

EXAMPLE 4963-Methyl-6-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinazolin-4(3H)-one

The title compound was prepared using the method for3-methyl-6-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoxalin-2(1H)-one.MS (ESI pos. ion) m/z: 369 (MH+). Calc'd exact mass for C₂₁H₁₆N₆O: 368.

(6-(5-cyclopropylisoxazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanamine

1) tert-butyl(6-vinyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate. To anargon purged flask were added4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (7.65 ml, 45.1 mmol),tert-butyl(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (3.20 g,11.3 mmol), cesium carbonate (11.0 g, 33.8 mmol), and PdCl₂(dppf)-CH₂Cl₂(0.461 g, 0.564 mmol). The mixture was dissolved in 38 mL of dioxane and4 mL of water (0.25M 10:1) and was heated to 80° C. for 12 h. Themixture was cooled to room temperature, concentrated, and purifieddirectly via MPLC (DCM/MeOH+1% NH₄OH) to afford the title compound (3.0g, 95% yield).

2) tert-butyl(6-formyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate.Tert-butyl (6-vinyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate(485 mg, 1.76 mmol) was dissolved in 5 mL of THF and 5 mL of water thenosmium tetroxide (0.687 mL (4% water solution), 0.0176 mmol) was addedand stirred for 5 min. Sodium periodate was added (141, 3.53 mmol) andthe reaction was stirred for 2 h. The reaction was then extracted withdichloromethane (3×10 mL), dried over Na₂SO₄ and concentrated.Purification via MPLC (DCM/MeOH+1% NH₄OH) afforded title compound as atan solid (350 mg, 72% yield).

3) (E)-tert-butyl(6-((hydroxyimino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate.Tert-butyl(6-formyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (400 mg,1.44 mmol) and hydroxylamine hydrochloride (200 mg, 2.86 mmol) werecombined in a flask with 25 mL of THF and 25 mL of 1 N NaOH solution.Stirred at rt for 1 h. Then added dichloromethane (50 mL) and extractedthe aqueous layer 3 times with DCM (50 mL), dried over Na₂SO₄ andconcentrated. Purified the oxime via MPLC (DCM/MeOH+1% NH₄OH) to givetitle compound (200 mg, 47% yield) as a tan solid.

4) (Z)-tert-butyl(6-(chloro(hydroxyimino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate.Dissolved (E)-tert-butyl(6-((hydroxyimino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate(200 mg, 0.684 mmol) in 25 mL of DMF and added1-chloropyrrolidine-2,5-dione (95.9 mg, 0.718 mmol). Let stir at rt for2 h. Poured reaction mixture onto water (20 mL) and extracted with ether(3×20 mL). Washed organics with water (2×20 mL), brine (1×20 ml), driedover sodium sulfate, filtered and concentrated. Title compound usedwithout further purification (220 mg, 97% yield).

5)(6-(5-cyclopropylisoxazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanamine.Dissolved (Z)-tert-butyl(6-(chloro(hydroxyimino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate(110 mg, 337 μmol), ethynylcyclopropane (28 μl, 337 μmol), and potassiumhydrogencarbonate (67.4 mg, 673 μmol) in 0.3 mL of EtOAc and heated to60° C. for 12 h to afford the protected intermediate. The solvent wasremoved by rotary evaporation and the residue was redissolved indicholoromethane (5 mL) and TFA (2 mL) and stirred for 30 min at roomtemperature. The solvent was then removed and the residue wasredissolved in MeOH. Solid K₂CO₃ was added and the mixture was stirredfor 1 h to free base the title compound. Purified the amine via MPLC(DCM/MeOH+1% NH₄OH) to afford the title compound (20 mg, 23% yield).

tert-butyl4-(8-chloro-1,5-naphthyridin-3-yl)-4-hydroxypiperidine-1-carboxylate

Dissolved 3-bromo-8-chloro-1,5-naphthyridine (210 mg, 862 μmol) in 8 mLof THF and cooled to −78° C. Then added butyllithium (517 μl, 1294 μmol)and stirred for 15 min. Added tert-butyl 4-oxopiperidine-1-carboxylate(258 mg, 1294 μmol) and let warm to room temperature over 1 h. Thereaction was quenched with saturated NH₄Cl and extracted withdichloromethane (3×20 mL), dried over NaSO₄ and concentrated.Intermediate was purified via MPLC (DCM/MeOH/NHOH) to yield tert-butyl4-(8-chloro-1,5-naphthyridin-3-yl)-4-hydroxypiperidine-1-carboxylate(120 mg, 38% yield.

EXAMPLE 4974-(8-((6-(3,5-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylamino)-1,5-naphthyridin-3-yl)piperidin-4-ol

Deprotection of tert-butyl4-(8-((6-(3,5-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylamino)-1,5-naphthyridin-3-yl)-4-hydroxypiperidine-1-carboxylateusing the method described for(6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanamine.M/Z=489.2 [M+H], calc 488.19 for C₂₅H₂₂F₂N₈O.

EXAMPLE 498N-((6-(3,5-difluorophenyl)-1,2,14-triazolo[4,3-b]pyridazin-3-yl)methyl)-7-(4-fluoropiperidin-4-yl)-1,5-naphthyridin-4-amine

A solution of tert-butyl4-(8-((6-(3,5-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylamino)-1,5-naphthyridin-3-yl)-4-hydroxypiperidine-1-carboxylate(30 mg, 51 μmol) in 0.5 mL of DCM was cooled to −78 C. Then added DAST(13 μl, 102 μmol) and let stir to room temperature over 30 min. TFA wasthen added to the reaction mixture and stirred for 30 min. The solventwas then removed by rotary evaporation and the residue was redissolvedin MeOH and free based through a cation exchange column. Purificationvia MPLC (DCM/MeOH+1% NH₄OH) yielded the title compound (15 mg, 60%yield). M/Z=491.2 [M+H], calc 490.18 for C₂₅H₂₁F₃N₈.

EXAMPLE 4996-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-3-methoxyquinoline

To a 5 ml CEM microwave tube was added tert-butyl2-(3-methoxyquinolin-6-yl)acetate (0.05 g, 0.2 mmol),1-(6-chloropyridazin-3-yl)hydrazine (0.04 g, 0.3 mmol), water (0.5 mL)and hydrochloric acid (0.05 ml, 0.5 mmol). The vial was sealed and firstheated at 90° C. for 30 min then placed into CEM microwave for 10 min.at 100° C., with 100 Watts of power via Powermax. The reaction mixturewas adjusted the pH to 7 by adding 5 N NaOH-brown ppt. was generated.The brown ppt. was dissolved in DCM. The organic was washed with water,dried over MgSO₄, and removed solvent in vacuo. The crude product waspurified using SiO₂ chromatography (Teledyne Isco RediSep®, P/N68-2203-026, 12 g SiO₂, DCM:EtOAc:MeOH=75%:20%:5%, Flow=30 mL/min). Apeak at 25 min was collected. The solvent was removed in vacuo to affordthe desired product as light yellowish solid. Wt: 20.0 mg. MS (ESI pos.ion) m/z: 326.53. Calc'd exact mass for C₁₆H₁₂ClN₅O: 325.75.

(R/S)-tert-butyl(6-(1-hydroxyethyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate

In a 10 mL round bottom flask under N₂ was dissolved tert-butyl(6-formyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (200 mg,721 μmol) in 3 mL of THF then cooled at −78° C. and treated withmethylmagnesium bromide (721 μl, 2164 μmol). After 30 minutes, thereaction mixture was warmed to 0° C. over 1 h. After 1 h the reactionmixture based on LC-MS was neutralized with NH₄Cl (sat.). The aqueousphase was extracted 3× with DCM then the organic layer was dried overNa₂SO₄, filtered and concentrated under reduced pressure. The crudetert-butyl(6-(1-hydroxyethyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate(202 mg, 95.5% yield) was used without further purification in the nextstep. MS m/z=294.4 [M+1]⁺. Calc'd for C₁₃H₁₉N₅O₃: 293.3.

EXAMPLE 500N-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxyquinolin-4-amine

a) 2-(7-methoxy-1,5-naphthyridin-4-ylamino)acetic acid hydrochloride. Ina 100 mL round bottom flask were dissolved8-chloro-3-methoxy-1,5-naphthyridine (5.00 g, 25.7 mmol) and glycinetert-butyl ester hydrochloride (17.2 g, 103 mmol) in 50 mL of 2-BuOHthen stirred and heated at 100° C. After 5 h the solvent based on LC-MSwas removed by reduced pressure and then the solid was dissolved in 200mL of HCl 1N and stirred at 60° C. overnight. After 10 h the reactionmixture based on LC-MS was cooled down to rt then 0° C. and the desiredacid precipitate. Filtered the solid (3.97 g) then evaporated theaqueous solution and triturated in 75 mL of H₂O at 0° C. then filteragain and washed with 25 mL of H₂O at 0° C. (1.58 g) to afforded total2-(7-methoxy-1,5-naphthyridin-4-ylamino)acetic acid hydrochloride (5.55g, 80.1% yield) as a tan solid. MS m/z=234.1 [M+H]⁺. Calc'd forC₁₁H₁₁N₃O₃: 233.1.

b)N-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine.In a 250 mL round bottom flask under N₂ were dissolved HATU (1762 mg,4635 μmol), 1-(6-chloropyridazin-3-yl)hydrazine (536 mg, 3708 μmol),2-(7-methoxy-1,5-naphthyridin-4-ylamino)acetic acid hydrochloride (1.00g, 3708 μmol) in 25 mL of MeCN then stirred and cooled down at −40° C.then treated with TRIETHYLAMINE (2584 μl, 18540 μmol) and warmed to rt.After 30 min the reaction mixture based on LC-MS was evaporated underreduced pressure and dry under high vacuum. The crude solid wasdissolved in 100 mL of i-PrOH then treated with Ts-OH (2821 mg, 14832μmol) and heated at 80° C. After 3 h the reaction mixture based on LC-MSwas diluted with DCM then neutralized with NaOH (1N). The aqueous phasewas extracted 3× with DCM with 10% MeOH then the organic layer was driedover Na₂SO₄, filtered and concentrated under reduced pressure. The crudemixture was triturated with hot i-PrOH then cooled down and filtered(662 mg) and the mother liquor was evaporated under reduced pressure andpurified by MPLC (ISCO) (210 mg) with DCM:MeOH 100:0 to 90:10 toafforded in combined yieldsN-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine(872 mg, 69% yield) as a off-white solid. MS m/z=342.1 [M+1]⁺. Calc'dfor C₁₅H₁₂ClN₇O: 341.7.

tert-Butyl(6-carbamoyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate

a)3-((tert-butoxycarbonyl)methyl)-[1,2,4]triazolo[4,3-b]pyridazine-6-carboxylicacid. In a 25 mL round bottom flask were dissolved 2-methyl-2-butene(21639 μl, 43278 μmol), potassium dihydrogen phosphate (2356 mg, 17311μmol) and tert-butyl(6-formyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (600 mg,2164 μmol) in 5 mL of t-BuOH and 5 mL of water then was added at 0° C.sodium chlorite (783 mg, 8656 μmol) and the reaction mixture was warmedto rt. After 10 h the reaction mixture based on LC-MS was concentratedunder reduced pressure and the crude acid was extract from the solidsalts mixture with MeOH, filtered and the solvent was concentrated underreduced pressure. The crude3-((tert-butoxycarbonyl)methyl)-[1,2,4]triazolo[4,3-b]pyridazine-6-carboxylicacid (635 mg, 100% yield) was used without further purification in thenext step. MS m/z=294.2 [M+1]⁺. Calc'd for C₁₂H₁₅N₅O₄: 293.1

b) tert-butyl(6-carbamoyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate. In a10 mL round bottom flask under N₂ were dissolved3-((tert-butoxycarbonyl)methyl)-[1,2,4]triazolo[4,3-b]pyridazine-6-carboxylicacid (250 mg, 852 μmol), HATU (389 mg, 1023 μmol), triethylamine (356μl, 2557 μmol) in 1.5 mL of DMF then was treated with a (92 μl, 4262μmol) and stirred at rt. After 2 h the reaction mixture based on LC-MSwas concentrated under reduced pressure and then purified by MPLC (ISCO)with DCM:MeOH+NH₄OH (1%) 100:0 to 90:10 to afforded tert-butyl(6-carbamoyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (129mg, 52% yield). MS m/z=293.2 [M+1]⁺. Calc'd for C₁₂H₁₆N₆O₃: 292.3.

3-(aminomethyl)-N-methyl-[1,2,4]triazolo[4,3-b]pyridazine-6-carboxamide

The title compound was made using the same conditions as tert-butyl(6-carbamoyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate.

EXAMPLE 5016-((6-chloro-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-3-methoxyquinoline

a) 1-(5-chloro-3-fluoronyridin-2-yl)hydrazine. A mixture of5-chloro-2,3-difluoropyridine (10.0 g, 66.9 mmol) and hydrazine (10.0ml, 319 mmol) in ^(i)PrOH (50 mL) was heated to 65-70° C. for 6 hours.The mixture was cooled to 23° C., filtered, and washed with Na₂CO₃(satd), and H₂O. Product isolated as a white solid. MS (ESI pos. ion)m/z: 162 (MH+). Calc'd exact mass for C₅H₅ClFN₃: 161.

b)6-((6-chloro-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)-3-methoxyquinolin.To a mixture of 2-(3-methoxyquinolin-6-yl)acetic acid (0.22 g, 1.0mmol), 1-(5-chloro-3-fluoropyridin-2-yl)hydrazine (0.11 g, 0.68 mmol)and triphenylphosphine (0.97 g, 2.0 mmol) (on solid support) in DCM (5mL) was added DIEA (0.24 ml, 1.4 mmol) followed by2,2,2-trichloroacetonitrile (0.14 ml, 1.4 mmol) via a syringe. Themixture was then heated to 150° C. for 15 minutes in an appropriatelysealed vial. The mixture was filtered and the filtrate was diluted with50 mL of EtOAc. The solution was washed with 30 mL of satd. NaHCO₃followed by 30 mL of brine, dried over Na₂SO₄ and concentrated in vacuo.The crude product was purified by a silica gel column chromatography(EtOAc to 10% MeOH/EtOAc) to give light yellow solid as desired product.MS (ESI pos. ion) m/z: 343 (MH+). Calc'd exact mass for C₁₇H₁₂ClFN₄O:342.

EXAMPLE 5023-Methoxy-6-((6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline

A flask charged with 5-bromo-3-methylisothiazole (0.049 g, 0.28 mmol)and 0.3 mL dry THF was cooled to 0° C., and isopropylmagnesium chloride(0.30 ml, 0.30 mmol) added dropwise over 5 minutes and the mixturestirred an additional 5 minutes before allowing to warm to rt. Themixture was stirred at rt 10 minutes and the mixture cannulated to asolution of zinc(II) chloride (0.30 ml, 0.30 mmol) [1M] and the slurrystirred 10 minutes. The zincate was treated with6-((6-iodo-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-3-methoxyquinoline(0.0890 g, 0.21 mmol), 1 mL dry THF, and a preformed solution of4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.012 g, 0.021mmol) and Pd(OAc)₂ (0.0024 g, 0.011 mmol) dissolved in 1 mL dry THF. Theflask was fitted with a reflux condenser and heated with a 90° C. oilbath for 24 h. The zincate portion of this procedure was repeated, addedto the reaction mixture, and the mixture heated at 90° C. for 1 h. Themixture was allowed to cool to rt and loaded onto 10 g of SiO₂wet-packed with THF, and eluted with 200 mL THF. The eluents wereconcentrated in vacuo, and taken up in 5 mL EtOH. To the solution wasadded Si-sulfonic acid (1.5 g, 1.1 mmol) and the mixture stirred at roomtemperature for 24 h, and the solid collected. The solid was washed withEtOH (discarded), and then 2M NH₃ in EtOH (5×5 mL). The ammoniacaleluents were concentrated and the residue purified by HPLC to afford3-methoxy-6-((6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline(0.0013 g, 1.6% yield).

1H NMR Data Example  4 (400 MHz, DMSO-d₆) □ ppm 8.54 (d, J = 9.73 Hz,1H), 8.51 (d, J = 2.78 Hz, 1H), 8.42 (d, J = 5.31 Hz, 1H), 8.09 (s, 1H),7.94 (d, J = 9.73 Hz, 2H), 7.58 (d, J = 2.78 Hz, 1H), 6.83 (d, J = 5.31Hz, 1H), 5.15 (d, J = 6.19 Hz, 1H), 3.94 (s, 1H), 3.94 (s, 3H), 2.52 (s,3H)  14 (400 MHz, DMSO-d₆) □ ppm 6.26 (s, 2H), 7.57-7.64 (m, 3H), 7.73(d, J = 5.56 Hz, 1H), 8.01 (d, J = 9.73 Hz, 1H), 8.07-8.13 (m, 2H), 8.35(d, J = 5.56 Hz, 1H), 8.47 (d, J = 9.73 Hz, 1H), 8.64 (s, 1H), 8.95 (s,1H)  34 (400 MHz, DMSO-d₆) □ ppm 2.39 (s, 3H) 3.95 (s, 3H) 5.16 (d, J =5.94 Hz, 2H) 6.82 (d, J = 5.43 Hz, 1H) 7.38 (s, 1H) 7.58 (d, J = 2.78Hz, 1H) 7.88 (d, J = 9.73 Hz, 1H) 7.95 (t, J = 5.87 Hz, 1H) 8.41 (d, J =5.31 Hz, 1H) 8.52 (d, J = 2.78 Hz, 1H) 8.55 (d, J = 9.73 Hz, 1H)  38(400 MHz, DMSO-d₆) □ ppm 3.88 (s, 3H) 6.00 (s, 2H) 6.52 (d, J = 7.58 Hz,1H) 7.13 (dd, J = 2.46 Hz, 2H) 7.27 (d, J = 5.31 Hz, 1H) 7.34 (d, J =2.40 Hz, 1H) 7.64 (t, J = 7.64 Hz, 1H) 7.80-8.11 (m, 3H) 8.75 (d, J =5.31 Hz, 1H) 9.24 (s, 1H) 11.42 (s, 1H)  39 (400 MHz, DMSO-d₆) □ ppm4.71 (s, 2H), 7.49 (d, J = 9.54 Hz, 1H), 7.51 (dd, J = 8.35, 3.51 Hz,1H), 7.75 (dd, J = 8.53, 1.51 Hz, 1H), 7.87 (s, 1H), 7.98 (d, J = 8.53Hz, 1H), 8.31 (d, J = 8.53 Hz, 1H), 8.46 (d, J = 10.04 Hz, 1H), 8.87 (d,J = 5.52 Hz, 1H)  40 (400 MHz, DMSO-d₆) □ ppm 3.89 (s, 3H), 4.79 (s,2H), 7.56-7.61 (m, 3H), 7.64 (dd, J = 8.61, 1.96 Hz, 1H), 7.72 (d, J =2.74 Hz, 1H), 7.83 (d, J = 1.37 Hz, 1H), 7.91 (d, J = 8.61 Hz, 1H), 7.96(d, J = 9.78 Hz, 1H), 8.07-8.12 (m, 2H), 8.45 (d, J = 9.78 Hz, 1H), 8.58(d, J = 2.93 Hz, 1H)  41 (400 MHz, MeOH) □ ppm 8.73 (s, 1H), 8.22 (d, J= 9.0 Hz, 1H), 7.87 (d, J = 4.3 Hz, 2H), 7.71-7.75 (m, 1H), 7.66 (d, J =9.0 Hz, 3H), 7.45-7.53 (m, 3H), 7.36-7.42 (m, 1H), 7.01-7.03 (m, 1H),6.91 (d, J = 2.2 Hz, 1H), 4.29 (s, 2H), 3.90 (s, 3H).  42 (400 MHz,DMSO-d₆) □ ppm 13.01 (s, 1H), 8.44 (d, J = 9.73 Hz, 1H), 8.18-8.30 (m,2H), 8.14 (s, 1H), 7.94-8.06 (m, 3H), 7.49-7.59 (m, 3H), 5.36 (s, 2H). 45 (400 MHz, MeOH) □ ppm 9.27 (s, 1H), 8.70 (d, J = 5.30 Hz, 1H), 8.41(d, J = 9.85 Hz, 1H), 8.06-8.10 (m, 2H), 7.90-7.99 (m, 2H), 7.62-7.67(m, 2H), 7.30-7.33 (m, 2H), 7.10-7.14 (m, 1H), 6.08 (s, 2H), 3.92 (s,3H).  51 (400 MHz, DMSO-d₆) □ ppm 13.98 (s, 1H), 9.82 (s, 1H), 8.73 (d,J = 1.26 Hz, 1H), 8.59 (s, 1H), 8.51 (d, J = 9.85 Hz, 1H), 8.16 (d, J =12.00 Hz, 1H), 8.07 (d, J = 9.73 Hz, 2H), 7.62-7.73 (m, 2H), 7.22 (d, J= 6.06 Hz, 1H), 5.43 (d, J = 5.68 Hz, 2H), 4.01 (s, 3H), 3.86 (t, J =6.95 Hz, 2H), 2.50-2.47 (m, 2H), 2.11-2.21 (m, 2H).  53 (400 MHz,DMSO-d₆) □ ppm 8.59 (s, 1H), 8.51 (d, J = 2.8 Hz, 1H), 8.41 (d, J = 5.5Hz, 1H), 8.34 (d, J = 9.7 Hz, 1H), 8.21-8.22 (m, 1H), 7.95-7.98 (m, 1H),7.73 (d, J = 9.7 Hz, 1H), 7.57 (d, J = 2.8 Hz, 1H), 6.83 (d, J = 5.2 Hz,1H), 5.13 (d, J = 6.3 Hz, 2H), 4.55-4.63 (m, 1H), 3.93 (s, 3H), 1.49 (s,3H), 1.47 (s, 3H).  56 (400 MHz, DMSO-d₆) □ ppm 3.87 (s, 3H), 5.84 (s,2H), 7.07-7.12 (m, 1H), 7.27-7.33 (m, 2H), 7.46-7.53 (m, 3H), 7.88-7.96(m, 2H), 8.01-8.06 (m, 2H), 8.12 (s, 1H), 8.30 (d, J = 9.47 Hz, 1H),8.72 (d, J = 5.18 Hz, 1H).  58 (400 MHz, DMSO-d₆) □ ppm 3.88 (s, 3H)5.86 (s, 2H) 7.09 (dd, J = 9.09, 2.27 Hz, 1H) 7.29 (d, J = 5.43 Hz, 1H)7.30-7.34 (m, 1H) 7.55-7.63 (m, 1H) 7.90-7.98 (m, 3H) 8.07-8.15 (m, 2H)8.33 (d, J = 9.60 Hz, 1H) 8.72 (d, J = 5.31 Hz, 1H)  60 (400 MHz,DMSO-d₆) □ ppm 3.32 (s, 3H) 6.09 (d, J = 0.88 Hz, 2H) 7.07 (dd, J =9.28, 2.46 Hz, 1H) 7.37 (d, J = 2.53 Hz, 1H) 7.47-7.54 (m, 2H) 7.55-7.60(m, 1H) 7.86-7.92 (m, 3H) 8.04 (d, J = 9.85 Hz, 1H) 8.52 (d, J = 9.85Hz, 1H) 8.89 (d, J = 3.79 Hz, 1H).  61 (400 MHz, DMSO-d₆) □ ppm 3.92 (s,3H) 5.07 (d, J = 6.19 Hz, 2H) 6.82 (d, J = 5.43 Hz, 1H) 7.54 (d, J =2.78 Hz, 1H) 7.88-7.91 (m, 2H) 8.00 (t, J = 6.20 Hz, 1H) 8.19-8.28 (m,3H) 8.38 (d, J = 5.43 Hz, 1H) 8.47 (d, J = 2.91 Hz, 1H).  65 (400 MHz,DMSO-d₆) □ ppm 8.53 (s, 1H), 8.40 (d, J = 5.05 Hz, 1H), 8.13-8.19 (m,2H), 8.00 (t, J = 6.00 Hz, 1H), 7.86 (s, 1H), 7.56-7.61 (m, 4H), 6.83(d, J = 5.31 Hz, 1H), 5.19 (d, J = 6.06 Hz, 2H), 3.93 (s, 3H), 2.67 (s,3H).  66 (400 MHz, DMSO-d₆) □ ppm 9.30 (s, 1H), 8.58 (s, 1H), 7.83 (d, J= 9.47 Hz, 1H), 7.67-7.73 (m, 3H), 7.51 (t, J = 7.58 Hz, 2H), 7.43 (t, J= 7.26 Hz, 1H), 7.14 (d, J = 8.34 Hz, 2H), 6.69 (d, J = 8.34 Hz, 2H),4.51 (s, 2H).  69 (400 MHz, DMSO-d₆) □ ppm 11.44 (s, 1H), 9.31 (s, 1H),8.53 (s, 1H), 7.65-7.76 (m, 2H), 7.13 (d, J = 8.08 Hz, 2H), 6.96 (s,1H), 6.69 (d, J = 8.34 Hz, 2H), 6.62 (s, 1H), 6.16 (s, 1H), 4.38 (s, 2H) 70 (300 MHz, DMSO-d₆) □ ppm 4.76 (s, 2H) 7.54-7.68 (m, 4H) 7.85 (dd, J= 8.33, 2.05 Hz, 1H) 7.95 (d, J = 9.79 Hz, 1H) 8.05 (s, 1H) 8.09-8.17(m, 2H) 8.19 (d, J = 1.90 Hz, 1H) 8.44 (d, J = 9.79 Hz, 1H).  77 (400MHz, DMSO-d₆) □ ppm 1.96 (d, J = 7.2 Hz, 3H), 5.15 (d, J = 7.2 Hz, 1H),7.50 (dd, J = 8.4, 4.1 Hz, 1H), 7.52-7.57 (m, 3H), 7.83 (dd, J = 8.7,1.9 Hz, 1H), 7.92 (d, J = 9.8 Hz, 1H), 7.97-8.03 (m, 4H), 8.35 (d, J =7.4 Hz, 1H), 8.42 (d, J = 9.8 Hz, 1H), 8.84 (dd, J = 4.1, 1.6 Hz, 1H). 89 (400 MHz, DMSO-d₆) □ ppm 9.23 (s, 1H), 8.74 (d, J = 5.05 Hz, 1H),8.19 (s, 1H), 7.86-7.97 (m, 3H), 7.70 (s, 1H), 7.34 (s, 1H), 7.24 (d, J= 5.05 Hz, 1H), 7.14 (dd, J = 9.16, 1.83 Hz, 1H), 5.98 (s, 2H), 3.89 (s,3H).  94 (400 MHz, DMSO-d₆) □ ppm 9.16 (t, J = 1.26 Hz, 1H), 8.68-8.75(m, 2H), 7.91-7.97 (m, 2H), 7.85-7.88 (m, 1H), 7.34 (d, J = 2.53 Hz,1H), 7.25 (d, J = 5.43 Hz, 1H), 7.14 (dd, J = 9.16, 2.59 Hz, 1H), 6.00(s, 2H), 3.89 (s, 3H), 3.26-3.32 (m, 2H), 1.11 (t, J = 7.20 Hz, 3H). 117(300 MHz, CHLOROFORM-d) δ ppm 2.09 (d, J = 7.31 Hz, 3H) 3.92 (s, 3H)5.08 (q, J = 7.21 Hz, 1H) 7.33 (d, J = 2.78 Hz, 1H) 7.48-7.55 (m, 4H)7.72 (dd, J = 8.62, 2.05 Hz, 1H) 7.77 (s, 1H) 7.84 (dd, J = 7.45, 2.19Hz, 2H) 8.01 (d, J = 8.62 Hz, 1H) 8.14 (d, J = 9.79 Hz, 1H) 8.62 (d, J =2.92 Hz, 1H). 118 (300 MHz, CHLOROFORM-d) δ ppm 2.09 (d, J = 7.31 Hz,3H) 3.92 (s, 3H) 5.08 (q, J = 7.31 Hz, 1H) 7.33 (d, J = 2.78 Hz, 1H)7.47-7.56 (m, 4H) 7.72 (dd, J = 8.55, 1.97 Hz, 1H) 7.77 (s, 1H) 7.84(dd, J = 7.45, 2.19 Hz, 2H) 8.01 (d, J = 8.62 Hz, 1H) 8.14 (d, J = 9.65Hz, 1H) 8.62 (d, J = 2.92 Hz, 1H). 119 (300 MHz, CHLOROFORM-d) δ ppm2.09 (d, J = 7.31 Hz, 3H) 3.92 (s, 3H) 5.08 (q, J = 7.21 Hz, 1H) 7.33(d, J = 2.78 Hz, 1H) 7.47-7.55 (m, 4H) 7.72 (dd, J = 8.62, 2.05 Hz, 1H)7.77 (s, 1H) 7.82-7.88 (m, 2H) 8.01 (d, J = 8.62 Hz, 1H) 8.14 (d, J =9.65 Hz, 1H) 8.62 (d, J = 2.92 Hz, 1H). 120 (300 MHz, CHLOROFORM-d) δppm 3.48 (s, 3H) 3.79-3.87 (m, 2H) 4.18-4.27 (m, 2H) 4.82 (s, 2H) 7.33(d, J = 2.78 Hz, 1H) 7.50-7.59 (m, 4H) 7.71 (d, J = 8.48 Hz, 1H) 7.78(s, 1H) 7.90-7.96 (m, 2H) 8.00 (d, J = 8.48 Hz, 1H) 8.15 (d, J = 9.65Hz, 1H) 8.68 (d, J = 2.92 Hz, 1H). 123 (400 MHz, DMSO-d₆) □ ppm 3.88 (s,3H), 6.02 (s, 2H), 7.12 (dd, J = 9.16, 2.46 Hz, 1H), 7.30-7.36 (m, 2H),7.50-7.61 (m, 3H), 7.97 (d, J = 9.22 Hz, 1H), 8.03-8.10 (m, 3H), 8.55(d, J = 9.73 Hz, 1H), 8.73 (d, J = 5.30 Hz, 1H) 125 (400 MHz, DMSO-d₆) □ppm 5.83 (s, 2H), 7.21 (d, J = 5.94 Hz, 2H), 7.55-7.63 (m, 3H), 8.06 (d,J = 9.73 Hz, 1H), 8.08-8.14 (m, 2H), 8.45 (d, J = 5.81 Hz, 2H), 8.53 (d,J = 9.60 Hz, 1H) 126 (400 MHz, DMSO-d₆) □ ppm 5.66 (s, 2H), 5.89 (s,2H), 6.18 (s, 1H), 6.31 (d, J = 3.92 Hz, 1H), 7.60 (s, 3H), 7.76 (d, J =5.68 Hz, 1H), 8.05 (d, J = 9.73 Hz, 1H), 8.08-8.16 (m, 2H), 8.53 (d, J =9.73 Hz, 1H) 131 (400 MHz, DMSO-d₆) □ ppm 2.81 (s, 3H), 3.88 (s, 3H),6.03 (s, 2H), 7.11 (d, J = 8.72 Hz, 1H), 7.28-7.38 (m, 2H), 7.92-8.02(m, 3H), 8.10 (d, J = 9.60 Hz, 1H), 8.15 (d, J = 7.58 Hz, 2H), 8.52-8.64(m, 2H), 8.73 (d, J = 4.42 Hz, 1H) 132 (400 MHz, DMSO-d₆) □ ppm 2.79 (d,J = 4.42 Hz, 3H), 3.89 (s, 3H), 6.05 (s, 2H), 7.12 (dd, J = 9.16, 2.46Hz, 1H), 7.31-7.35 (m, 2H), 7.76 (t, J = 7.64 Hz, 1H), 7.95-8.05 (m,3H), 8.12 (d, J = 9.85 Hz, 1H), 8.39 (d, J = 4.80 Hz, 1H), 8.60 (d, J =9.85 Hz, 1H), 8.73 (d, J = 5.18 Hz, 1H) 135 (400 MHz, DMSO-d₆) □ ppm2.77 (d, J = 4.55 Hz, 3H), 3.88 (s, 3H), 6.05 (s, 2H), 7.12 (dd, J =9.16, 2.34 Hz, 1H), 7.32 (d, J = 5.31 Hz, 1H), 7.34 (s, 1H), 7.58 (d, J= 7.96 Hz, 1H), 7.98 (d, J = 9.09 Hz, 1H), 8.08 (d, J = 8.08 Hz, 1H),8.12 (d, J = 9.85 Hz, 1H), 8.18 (s, 1H), 8.42-8.50 (m, 1H), 8.58 (d, J =9.85 Hz, 1H), 8.73 (d, J = 5.31 Hz, 1H) 155 (400 MHz, DMSO-d₆) □ ppm3.94 (s, 3H) 5.25 (d, J = 6.19 Hz, 2H) 6.89 (d, J = 5.68 Hz, 1H) 7.57(d, J = 2.65 Hz, 1H) 7.88 (t, J = 1.83 Hz, 1H) 8.07 (d, J = 9.73 Hz, 1H)8.27 (d, J = 1.77 Hz, 3H) 8.43 (d, J = 5.56 Hz, 1H) 8.50 (d, J = 9.85Hz, 1H) 8.55 (d, J = 2.78 Hz, 1H) 155 (400 MHz, DMSO-d₆) □ ppm 3.94 (s,3H) 5.25 (d, J = 6.19 Hz, 2H) 6.89 (d, J = 5.68 Hz, 1H) 7.57 (d, J =2.65 Hz, 1H) 7.88 (t, J = 1.83 Hz, 1H) 8.07 (d, J = 9.73 Hz, 1H) 8.27(d, J = 1.77 Hz, 3H) 8.43 (d, J = 5.56 Hz, 1H) 8.50 (d, J = 9.85 Hz, 1H)8.55 (d, J = 2.78 Hz, 1H) 157 (400 MHz, DMSO-d₆) □ ppm 3.93 (s, 3H) 5.23(d, J = 6.19 Hz, 2H) 6.85 (d, J = 5.18 Hz, 1H) 7.57 (d, J = 2.65 Hz, 1H)7.85 (t, J = 7.83 Hz, 1H) 7.93-8.04 (m, 2H) 8.10 (d, J = 9.85 Hz, 1H)8.40 (d, J = 5.43 Hz, 1H) 8.45-8.54 (m, 4H) 157 (400 MHz, DMSO-d₆) □ ppm3.93 (s, 3H) 5.23 (d, J = 6.19 Hz, 2H) 6.85 (d, J = 5.18 Hz, 1H) 7.57(d, J = 2.65 Hz, 1H) 7.85 (t, J = 7.83 Hz, 1H) 7.93-8.04 (m, 2H) 8.10(d, J = 9.85 Hz, 1H) 8.40 (d, J = 5.43 Hz, 1H) 8.45-8.54 (m, 4H) 158(400 MHz, DMSO-d₆) □ ppm 8.63 (d, J = 5.31 Hz, 1H), 8.49 (d, J = 9.73Hz, 1H), 8.02 (t, J = 9.54 Hz, 2H), 7.93 (d, J = 7.20 Hz, 2H), 7.56 (t,J = 7.20 Hz, 1H), 7.50 (t, J = 7.39 Hz, 2H), 7.31 (d, J = 2.40 Hz, 1H),7.16 (d, J = 5.43 Hz, 1H), 7.12 (dd, J = 9.22, 2.53 Hz, 1H), 6.61 (q, J= 6.44 Hz, 1H), 3.87 (s, 3H), 2.07 (d, J = 6.57 Hz, 3H) 159 (400 MHz,DMSO-d₆) □ ppm 8.46 (d, J = 9.73 Hz, 1H), 8.32 (d, J = 5.31 Hz, 1H),8.19 (s, 1H), 8.12-8.18 (m, 2H), 7.99 (d, J = 9.85 Hz, 1H), 7.85 (t, J =5.49 Hz, 1H), 7.53-7.63 (m, 3H), 7.17 (d, J = 2.53 Hz, 1H), 7.07 (dd, J= 9.16, 2.59 Hz, 1H), 6.66 (d, J = 5.43 Hz, 1H), 5.13 (d, J = 5.56 Hz,2H), 3.85 (s, 3H) 160 (400 MHz, DMSO-d₆) □ ppm 8.69 (d, J = 4.67 Hz,1H), 8.46 (d, J = 9.85 Hz, 1H), 8.08-8.16 (m, 2H), 8.00 (d, J = 9.73 Hz,1H), 7.95 (d, J = 9.22 Hz, 1H), 7.77 (d, J = 4.80 Hz, 1H), 7.56-7.65 (m,3H), 7.36 (d, J = 2.40 Hz, 1H), 7.23 (dd, J = 9.22, 2.40 Hz, 1H), 5.12(s, 2H), 3.89 (s, 3H) 161 (400 MHz, DMSO-d₆) □ ppm 8.52 (d, J = 2.78 Hz,1H), 8.45 (d, J = 9.85 Hz, 1H), 8.41 (d, J = 5.30 Hz, 1H), 8.14-8.21 (m,2H), 7.94-8.04 (m, 2H), 7.54-7.63 (m, 4H), 6.85 (d, J = 5.31 Hz, 1H),5.20 (d, J = 6.06 Hz, 2H), 3.93 (s, 3H) 171 (400 MHz, DMSO-d₆) □ ppm8.52 (d, J = 2.78 Hz, 1H), 8.48 (d, J = 9.73 Hz, 1H), 8.40 (d, J = 5.31Hz, 1H), 8.34-8.40 (m, 1H), 8.05-8.15 (m, 2H), 8.02 (d, J = 9.85 Hz,1H), 7.63-7.77 (m, 1H), 7.57 (d, J = 2.78 Hz, 1H), 6.85 (d, J = 5.56 Hz,1H), 5.21 (d, J = 6.19 Hz, 2H), 3.93 (s, 3H) 172 (400 MHz, DMSO-d₆) □ppm 8.51 (d, J = 6.19 Hz, 1H), 8.50 (s, 1H), 8.40 (d, J = 5.31 Hz, 1H),8.23-8.33 (m, 2H), 8.12 (t, J = 5.68 Hz, 1H), 8.03 (d, J = 9.85 Hz, 1H),7.56 (d, J = 2.53 Hz, 1H), 6.86 (d, J = 5.43 Hz, 1H), 5.21 (d, J = 6.06Hz, 2H), 3.93 (s, 3H) 176 (400 MHz, DMSO-d₆) □ ppm 8.51 (d, J = 2.91 Hz,1H), 8.36-8.43 (m, 2H), 7.85-7.95 (m, 3H), 7.57 (d, J = 2.78 Hz, 1H),7.47 (s, 1H), 6.83 (d, J = 5.31 Hz, 1H), 5.11 (d, J = 5.94 Hz, 2H), 3.94(s, 3H), 2.29 (s, 3H) 182 (300 MHz, DMSO-d₆) □ ppm 2.56 (s, 4H),2.59-2.68 (m, 1H), 4.09 (s, 2H), 6.87 (dd, J = 5.92, 2.27 Hz, 1H), 7.21(s, 1H), 7.63 (s, 1H), 7.65 (d, J = 1.75 Hz, 1H), 8.08-8.16 (m, 2H),8.17 (d, J = 1.75 Hz, 2H), 8.58 (d, J = 9.79 Hz, 1H), 9.10 (s, 1H) 184(400 MHz, DMSO-d₆) □ ppm 8.73 (d, J = 5.18 Hz, 1H), 8.48-8.55 (m, 2H),8.03 (d, J = 9.85 Hz, 1H), 7.96 (d, J = 9.09 Hz, 1H), 7.70-7.75 (m, 2H),7.30-7.35 (m, 2H), 7.12 (dd, J = 9.22, 2.40 Hz, 1H), 5.98 (s, 2H), 3.88(s, 3H). 194 (400 MHz, MeOH) □ ppm 8.69 (d, J = 4.93 Hz, 1H), 8.35 (d, J= 9.85 Hz, 1H), 8.08 (d, J = 9.22 Hz, 1H), 8.00 (d, J = 9.85 Hz, 1H),7.85-7.93 (m, 2H), 7.29-7.33 (m, 2H), 7.10-7.20 (m, 2H), 6.05 (s, 2H),3.93 (s, 3H), 2.28 (s, 3H). 198 (400 MHz, MeOH) □ ppm 8.68 (d, J = 5.43Hz, 1H), 8.42 (d, J = 9.73 Hz, 2H), 8.26 (d, J = 6.82 Hz, 1H), 8.06 (dd,J = 9.47, 2.78 Hz, 2H), 7.78 (d, J = 8.72 Hz, 1H), 7.28-7.31 (m, 2H),7.08-7.12 (m, 1H), 6.07 (s, 2H), 3.92 (s, 3H). 215 (400 MHz, DMSO-d₆) □ppm 2.33 (s, 3H) 3.96 (s, 3H) 6.00 (s, 2H) 7.19 (dd, J = 9.16, 2.46 Hz,1H) 7.38 (d, J = 5.31 Hz, 1H) 7.40 (d, J = 2.27 Hz, 1H) 7.48 (s, 1H)7.99 (s, 1H) 8.01-8.10 (m, 2H) 8.54 (d, J = 9.73 Hz, 1H) 8.80 (d, J =5.31 Hz, 1H) 219 (400 MHz, DMSO-d₆) □ ppm 3.89 (s, 3H) 6.06 (s, 2H) 7.12(d, J = 9.09 Hz, 1H) 7.29-7.38 (m, 2H) 7.51 (t, J = 9.03 Hz, 1H) 7.86(d, J = 6.44 Hz, 2H) 7.98 (d, J = 9.09 Hz, 1H) 8.12 (d, J = 9.98 Hz, 1H)8.62 (d, J = 9.35 Hz, 1H) 8.74 (d, J = 4.80 Hz, 1H) 220 (400 MHz,DMSO-d₆) □ ppm 3.90 (s, 3H) 6.06 (s, 2H) 7.13 (d, J = 8.59 Hz, 1H) 7.32(d, J = 5.05 Hz, 1H) 7.35 (s, 1H) 7.99 (d, J = 9.35 Hz, 1H) 8.05-8.15(m, 3H) 8.62 (d, J = 9.73 Hz, 1H) 8.74 (d, J = 5.05 Hz, 1H) 222 (400MHz, DMSO-d₆) □ ppm 2.50 (s, 3H) 3.89 (s, 3H) 5.98 (s, 2H) 7.12 (d, J =8.84 Hz, 1H) 7.32 (d, J = 14.91 Hz, 2H) 7.93-8.06 (m, 2H) 8.09 (s, 1H)8.63 (d, J = 8.97 Hz, 1H) 8.74 (s, 1H) 224 (400 MHz, DMF) □ ppm 4.31 (s,3H) 6.49 (s, 2H) 7.55 (dd, J = 8.84, 2.02 Hz, 1H) 7.74 (d, J = 5.18 Hz,1H) 7.76 (s, 1H) 8.27 (s, 1H) 8.41 (d, J = 9.22 Hz, 1H) 8.54 (d, J =1.14 Hz, 2H) 8.58 (s, 1H) 9.02 (d, J = 9.60 Hz, 1H) 9.16 (d, J = 5.31Hz, 1H) 233 (400 MHz, DMSO-d₆) □ ppm 3.89 (s, 3H) 3.90 (s, 3H) 5.93 (s,2H) 7.13 (dd, J = 9.16, 2.59 Hz, 1H) 7.30 (d, J = 5.31 Hz, 1H) 7.34 (d,J = 2.40 Hz, 1H) 7.79 (d, J = 9.73 Hz, 1H) 7.96 (d, J = 9.22 Hz, 1H)8.09 (s, 1H) 8.44 (d, J = 9.73 Hz, 1H) 8.46 (s, 1H) 8.73 (d, J = 5.30Hz, 1H). 234 (400 MHz, DMSO-d₆) □ ppm 3.93 (s, 3H) 3.94 (s, 3H) 5.12 (d,J = 6.19 Hz, 2H) 6.82 (d, J = 5.43 Hz, 1H) 7.57 (d, J = 2.78 Hz, 1H)7.70 (d, J = 9.73 Hz, 1H) 7.96 (t, J = 6.19 Hz, 1H) 8.21 (s, 1H) 8.34(d, J = 9.73 Hz, 1H) 8.41 (d, J = 5.43 Hz, 1H) 8.51 (d, J = 2.78 Hz, 1H)8.52 (s, 1H). 238 (400 MHz, DMSO-d₆) □ ppm 1.37 (t, J = 6.95 Hz, 3H),3.89 (s, 3H), 4.19 (q, J = 6.95, 2H), 6.01 (s, 2H), 7.12 (dd, J = 8.91,2.46 Hz, 1H), 7.28-7.36 (m, 3H), 7.92 (d, J = 7.71 Hz, 1H), 7.97 (d, J =9.09 Hz, 2H), 8.06 (d, J = 9.85 Hz, 1H), 8.51 (d, J = 9.85 Hz, 1H), 8.73(d, J = 5.18 Hz, 1H) 245 (400 MHz, DMSO-d₆) □ ppm 3.88 (s, 3H), 6.03 (s,2H), 7.12 (dd, J = 9.16, 2.46 Hz, 1H), 7.25 (d, J = 5.31 Hz, 1H),7.27-7.31 (m, 1H), 7.34 (d, J = 2.53 Hz, 1H), 7.50-7.59 (m, 1H),7.63-7.74 (m, 2H), 7.90-8.00 (m, 2H), 8.74 (d, J = 5.31 Hz, 1H), 9.02(s, 1H) 245 (400 MHz, DMSO-d₆) □ ppm 3.88 (s, 3H), 6.04 (s, 2H), 7.13(d, J = 10.86 Hz, 1H), 7.24 (d, J = 5.31 Hz, 1H), 7.34 (s, 1H), 7.45 (d,J = 6.44 Hz, 1H), 7.50 (t, J = 6.63 Hz, 2H), 7.78 (d, J = 7.45 Hz, 2H),7.89 (d, J = 12.25 Hz, 1H), 7.97 (d, J = 9.22 Hz, 1H), 8.74 (d, J = 6.19Hz, 1H), 8.94 (s, 1H) 247 (400 MHz, DMSO-d₆) □ ppm 3.91 (s, 3H), 5.16(d, J = 5.94 Hz, 1H), 6.91 (d, J = 5.31 Hz, 1H), 7.32 (t, J = 8.34 Hz,1H), 7.55 (d, J = 2.53 Hz, 1H), 7.57-7.63 (m, 1H), 7.64-7.74 (m, 2H),7.83 (d, J = 12.51 Hz, 1H), 8.34-8.45 (m, 2H), 8.50 (d, J = 2.53 Hz,1H), 9.11 (s, 2H) 252 (400 MHz, DMSO-d₆) □ ppm 3.88 (s, 3H) 6.02 (s, 2H)7.12 (dd, J = 9.16 Hz, 1H) 7.25 (d, J = 5.31 Hz, 1H) 7.30-7.42 (m, 3H)7.73-7.89 (m, 3H) 7.89-8.01 (m, 2H) 8.73 (d, J = 5.31 Hz, 1H) 9.01 (s,1H) 252 (400 MHz, DMSO-d₆) □ ppm 3.88 (s, 3H) 6.02 (s, 2H) 7.12 (dd, J =9.16 Hz, 1H) 7.25 (d, J = 5.31 Hz, 1H) 7.30-7.42 (m, 3H) 7.73-7.89 (m,3H) 7.89-8.01 (m, 2H) 8.73 (d, J = 5.31 Hz, 1H) 9.01 (s, 1H) 254 (400MHz, DMSO-d₆) □ ppm 3.88 (s, 3H) 6.00 (s, 2H) 7.12 (dd, J = 9.09 Hz, 1H)7.26 (d, J = 5.43 Hz, 1H) 7.33 (d, J = 2.40 Hz, 1H) 7.51-7.71 (m, 2H)7.81-8.02 (m, 4H) 8.74 (d, J = 5.30 Hz, 1H) 9.08 (s, 1H) 259 (400 MHz,DMSO-d₆) □ ppm 2.76 (d, J = 4.29 Hz, 3H) 3.88 (s, 3H) 6.03 (s, 2H) 7.13(d, J = 8.84 Hz, 1H) 7.26 (d, J = 5.05 Hz, 1H) 7.33 (s, 1H) 7.54 (d, J =7.58 Hz, 1H) 7.79 (d, J = 7.83 Hz, 1H) 7.85-8.04 (m, 4H) 8.39 (d, J =3.66 Hz, 1H) 8.74 (d, J = 5.31 Hz, 1H) 9.12 (s, 1H) 263 (400 MHz,DMSO-d₆) □ ppm 3.88 (s, 3H) 6.00 (s, 2H) 7.12 (dd, J = 9.09 Hz, 1H) 7.26(d, J = 5.18 Hz, 1H) 7.33 (d, J = 2.27 Hz, 1H) 7.65-7.69 (m, 1H)7.69-7.74 (m, 1H) 7.92-7.97 (m, 3H) 8.08 (d, J = 2.27 Hz, 1H) 8.74 (d, J= 5.18 Hz, 1H) 9.07 (s, 1H) 266 (400 MHz, DMSO-d₆) □ ppm 3.88 (s, 3H)6.01 (s, 2H) 7.11 (dd, J = 9.22 Hz, 1H) 7.26 (d, J = 5.30 Hz, 1H)7.29-7.37 (m, 2H) 7.60 (d, J = 6.95 Hz, 2H) 7.89-8.01 (m, 3H) 8.75 (d, J= 5.31 Hz, 1H) 9.16 (s, 1H) 267 (400 MHz, DMSO-d₆) □ ppm 3.88 (s, 3H)5.99 (s, 2H) 7.11 (dd, J = 2.40 Hz, 1H) 7.26 (d, J = 5.31 Hz, 1H) 7.34(d, J = 2.27 Hz, 1H) 7.79-7.93 (m, 3H) 7.93-8.04 (m, 2H) 8.75 (d, J =5.31 Hz, 1H) 9.14 (s, 1H) 270 (400 MHz, DMSO-d₆) □ ppm 3.89 (s, 3H) 6.01(s, 2H) 7.14 (dd, J = 9.16 Hz, 1H) 7.22-7.26 (m, 2H) 7.35 (d, J = 2.53Hz, 1H) 7.55 (d, J = 3.92 Hz, 1H) 7.78 (dd, J = 9.60 Hz, 1H) 7.93-8.00(m, 2H) 8.74 (d, J = 5.31 Hz, 1H) 8.97 (t, 1H) 279 (400 MHz, DMSO-d₆) □ppm 2.50 (s, 3H) 3.89 (s, 3H) 6.06 (s, 2H) 7.13 (d, J = 7.58 Hz, 1H)7.25 (d, J = 2.40 Hz, 1H) 7.35 (s, 1H) 7.66 (s, 1H) 7.91-8.01 (m, 3H)8.74 (d, J = 5.68 Hz, 1H) 9.18 (s, 1H) 283 (400 MHz, DMSO-d₆) □ ppm 3.88(s, 3H) 5.92 (s, 2H) 6.15 (s, 1H) 6.69 (s, 1H) 6.94 (s, 1H) 7.12 (dd, J= 8.91, 1.96 Hz, 1H) 7.29 (d, J = 5.18 Hz, 1H) 7.34 (d, J = 1.77 Hz, 1H)7.81-7.90 (m, 2H) 7.98 (d, J = 9.22 Hz, 1H) 8.76 (d, J = 5.18 Hz, 1H)8.88 (s, 1H) 11.49 (s, 1H). 284 (400 MHz, DMSO-d₆) □ ppm 3.88 (s, 3H)6.03 (s, 2H) 7.13 (dd, J = 9.16, 2.34 Hz, 1H) 7.25 (d, J = 5.30 Hz, 1H)7.33 (d, J = 2.15 Hz, 1H) 7.43 (t, J = 7.14 Hz, 1H) 7.50 (t, J = 7.45Hz, 2H) 7.75 (d, J = 7.45 Hz, 2H) 7.85 (d, J = 8.72 Hz, 1H) 7.96 (d, J =9.22 Hz, 2H) 8.74 (d, J = 5.31 Hz, 1H) 9.00 (s, 1H). 285 (400 MHz,DMSO-d₆) □ ppm 3.89 (s, 3H) 6.03 (s, 2H) 7.11-7.21 (m, 2H) 7.24 (d, J =5.30 Hz, 1H) 7.34 (d, J = 2.27 Hz, 1H) 7.62-7.67 (m, 2H) 7.81 (dd, J =9.60, 1.14 Hz, 1H) 7.96 (dd, J = 16.55, 9.35 Hz, 2H) 8.73 (d, J = 5.18Hz, 1H) 8.96 (s, 1H). 287 (400 MHz, DMSO-d₆) □ ppm 2.23 (s, 3H) 3.89 (s,3H) 6.02 (s, 2H) 7.14 (dd, J = 9.16, 2.46 Hz, 1H) 7.20-7.26 (m, 2H) 7.34(d, J = 2.53 Hz, 1H) 7.47 (s, 1H) 7.76 (dd, J = 9.66, 1.45 Hz, 1H) 7.94(dd, J = 18.88, 9.41 Hz, 2H) 8.74 (d, J = 5.18 Hz, 1H) 8.92 (s, 1H). 290(400 MHz, DMSO-d₆) □ ppm 3.89 (s, 3H) 6.02 (s, 2H) 7.15 (dd, J = 9.28,2.34 Hz, 1H) 7.25 (d, J = 5.31 Hz, 1H) 7.35 (d, J = 2.27 Hz, 1H) 7.87(d, J = 10.36 Hz, 1H) 7.98 (d, J = 8.84 Hz, 2H) 8.45 (s, 1H) 8.74 (d, J= 5.43 Hz, 1H) 9.06 (s, 1H) 9.17 (s, 1H) 291 (400 MHz, DMSO-d₆) □ ppm2.46 (s, 3H) 3.89 (s, 3H) 6.01 (s, 2H) 7.14 (dd, J = 9.22, 2.53 Hz, 1H)7.25 (d, J = 5.31 Hz, 1H) 7.35 (d, J = 2.40 Hz, 1H) 7.73 (s, 1H) 7.77(dd, J = 9.60, 1.52 Hz, 1H) 7.97 (d, J = 9.22 Hz, 1H) 8.00 (d, J = 9.60Hz, 1H) 8.75 (d, J = 5.31 Hz, 1H) 9.19 (s, 1H) 295 (400 MHz, DMSO-d₆) □ppm 3.93 (s, 3H) 5.14 (d, J = 5.94 Hz, 2H) 6.91 (d, J = 5.18 Hz, 1H)7.57 (d, J = 2.02 Hz, 1H) 7.73 (s, 1H) 7.76 (d, J = 11.37 Hz, 1H) 8.35(t, J = 6.00 Hz, 1H) 8.43 (d, J = 4.80 Hz, 1H) 8.53 (d, J = 2.53 Hz, 1H)9.17 (s, 1H) 297 (400 MHz, DMSO-d₆) □ ppm 2.30 (s, 3H) 3.89 (s, 3H) 6.03(s, 2H) 7.07 (s, 1H) 7.13 (dd, J = 9.09, 2.53 Hz, 1H) 7.25 (d, J = 5.43Hz, 1H) 7.35 (d, J = 2.40 Hz, 1H) 7.88 (dd, J = 9.73, 1.39 Hz, 1H) 7.96(d, J = 9.22 Hz, 1H) 8.04 (d, J = 9.60 Hz, 1H) 8.75 (d, J = 5.31 Hz, 1H)9.29 (s, 1H) 298 (400 MHz, DMSO-d₆) □ ppm 3.93 (s, 3H) 5.16 (d, J = 5.94Hz, 2H) 6.91 (d, J = 5.43 Hz, 1H) 7.56 (d, J = 2.27 Hz, 1H) 7.83-7.94(m, 3H) 8.34 (t, J = 5.75 Hz, 1H) 8.43 (d, J = 5.18 Hz, 1H) 8.52 (d, J =2.27 Hz, 1H) 9.14 (s, 1H) 302 (400 MHz, DMSO-d₆) □ ppm 2.22 (s, 3H),3.88 (s, 3H), 6.03 (s, 2H), 7.04-7.42 (m, 4H), 7.50 (s, 1H), 7.79 (d, J= 9.47 Hz, 1H), 7.97 (d, J = 6.06, 1H), 8.76 (d, J = 18.95, 2H) 306 (400MHz, CHLOROFORM-d) □ ppm 4.72 (s, 1H) 7.27 (dd, J = 9.59, 1.56 Hz, 1H)7.41 (dd, J = 8.31, 4.21 Hz, 1H) 7.62-7.66 (m, 2H) 7.69 (dd, J = 9.68,0.88 Hz, 1H) 7.87-7.91 (m, 1H) 8.05-8.12 (m, 2H) 8.92 (dd, J = 4.21,1.66 Hz, 1H 307 (400 MHz, DMSO-d₆) □ ppm 5.03 (s, 2H) 7.49 (t, J = 7.34Hz, 1H) 7.57 (t, J = 7.43 Hz, 3H) 7.84 (d, J = 7.43 Hz, 2H) 7.93-8.02(m, 1H) 8.08 (d, J = 9.59 Hz, 1H) 8.12-8.20 (m, 2H) 8.27 (s, 1H) 8.35(d, J = 7.82 Hz, 1H) 9.00 (d, J = 6.46 Hz, 1H) 9.11 (d, J = 5.09 Hz, 1H)9.22 (d, J = 3.91 Hz, 1H). 308 (400 MHz, DMSO-d₆) □ ppm 2.32 (s, 3H)5.00 (s, 2H) 7.92 (d, J = 9.54 Hz, 1H) 8.01 (t, J = 15.56, 6.53 Hz, 2H)8.16 (d, J = 8.53 Hz, 1H) 8.25 (s, 1H) 8.37 (d, J = 9.03 Hz, 1H) 9.04(d, J = 8.03 Hz, 1H) 9.21 (s, 1H) 9.23 (d, J = 4.52 Hz, 1H) 315 (400MHz, DMSO-d₆) □ ppm 5.06 (s, 2H), 7.52-7.62 (m, 3H), 7.62-7.71 (m, 1H),7.83 (d, J = 7.07 Hz, 1H), 7.93 (d, J = 9.73 Hz, 1H), 8.01-8.11 (m, 3H),8.21 (d, J = 6.06 Hz, 1H), 8.41 (d, J = 9.85 Hz, 1H), 8.55 (d, J = 5.94Hz, 1H), 9.32 (s, 1H) 323 (400 MHz, CDCl₃) □ ppm 3.84 (t, J = 7.33 Hz,2H), 3.93-4.00 (m, 5H), 7.33 (d, J = 4.42 Hz, 1H), 7.48-7.56 (m, 4H),7.59 (s, 1H), 7.85 (dd, J = 7.45, 1.77 Hz, 2H), 8.11 (d, J = 9.73 Hz,1H), 8.69 (d, J = 4.42 Hz, 1H), 8.72 (d, J = 2.90 Hz, 1H) 328 (300 MHz,DMSO-d₆) □ ppm 4.48 (s, 2H) 6.90 (d, J = 8.33 Hz, 1H) 7.14 (dd, J =8.11, 1.39 Hz, 1H) 7.42 (d, J = 1.46 Hz, 1H) 7.53-7.71 (m, 3H) 7.94 (d,J = 9.79 Hz, 1H) 8.05-8.22 (m, 2H) 8.42 (d, J = 9.79 Hz, 1H), 10.2 (br,1H). 332 (300 MHz, DMSO-d₆) □ ppm 2.01 (s, 3H) 3.34 (s, 1H) 4.53 (s, 2H)7.32 (d, J = 7.60 Hz, 2H) 7.51 (d, J = 7.45 Hz, 2H) 7.59 (s, 3H) 7.94(d, J = 9.50 Hz, 1H) 8.11 (s, 2H) 8.42 (d, J = 9.65 Hz, 1H) 9.89 (s,1H). 336 (300 MHz, MeOH) δ ppm 2.31 (s, 3H) 4.79 (s, 2H) 7.29 (s, 1H)7.51 (dd, J = 8.33, 4.38 Hz, 1H) 7.70 (s, 1H) 7.82 (d, J = 9.79 Hz, 1H)7.85-7.90 (m, 1H) 7.95-8.01 (m, 1H) 8.03 (s, 1H) 8.14 (d, J = 9.79 Hz,1H) 8.34 (d, J = 8.62 Hz, 1H) 8.79 (dd, J = 4.31, 1.68 Hz, 1H). 337 (300MHz, CHLOROFORM-d) δ ppm 4.85 (s, 2H) 7.35-7.48 (m, 2H) 7.57 (dd, J =8.18, 6.43 Hz, 2H) 7.82 (d, J = 8.62 Hz, 1H) 7.91 (s, 1H) 8.08 (d, J =8.62 Hz, 1H) 8.13 (d, J = 8.33 Hz, 1H) 8.21 (d, J = 9.79 Hz, 1H) 8.90(d, J = 4.24 Hz, 1H). 338 (300 MHz, CHLOROFORM-d) δ ppm 4.85 (s, 2H)6.97-7.06 (m, 1H) 7.35-7.43 (m, 1H) 7.43-7.51 (m, 3H) 7.84 (d, J = 8.62Hz, 1H) 7.93 (t, J = 4.90 Hz, 1H) 8.08 (d, J = 8.48 Hz, 1H) 8.13 (d, J =8.77 Hz, 1H) 8.20 (d, J = 9.65 Hz, 1H) 8.89 (dd, J = 4.17, 1.68 Hz, 1H).339 (300 MHz, CHLOROFORM-d) δ ppm 4.84 (s, 2H) 7.17-7.26 (m, 2H) 7.39(dd, J = 8.18, 4.24 Hz, 1H) 7.51 (d, J = 9.79 Hz, 1H) 7.85 (dd, J =8.70, 1.97 Hz, 1H) 7.88-7.96 (m, 3H) 8.01-8.13 (m, 2H) 8.16 (d, J = 9.79Hz, 1H) 8.89 (dd, J = 4.24, 1.61 Hz, 1H). 340 (300 MHz, CHLOROFORM-d) δppm 4.84 (s, 2H) 7.34 (d, J = 9.65 Hz, 1H) 7.40 (dd, J = 8.18, 4.24 Hz,1H) 7.48 (d, J = 9.65 Hz, 1H) 7.61-7.69 (m, 1H) 7.74-7.80 (m, 1H) 7.83(dd, J = 8.62, 2.05 Hz, 1H) 7.90 (s, 1H) 8.08 (d, J = 8.62 Hz, 1H) 8.12(d, J = 9.06 Hz, 1H) 8.18 (d, J = 9.79 Hz, 1H) 8.89 (dd, J = 4.17, 1.68Hz, 1H). 341 (300 MHz, CHLOROFORM-d) δ ppm 4.01 (s, 3H) 4.79 (s, 2H)7.25 (s, 1H) 7.38 (dd, J = 8.33, 4.24 Hz, 1H) 7.81-7.89 (m, 2H) 7.91 (s,1H) 8.00 (s, 1H) 8.03-8.10 (m, 2H) 8.11 (s, 1H) 8.88 (dd, J = 4.24, 1.61Hz, 1H). 342 (300 MHz, DMSO-d₆) δ ppm 4.74 (s, 2H) 7.45 (d, J = 2.63 Hz,1H) 7.53 (dd, J = 8.62, 1.90 Hz, 1H) 7.56-7.61 (m, 3H) 7.79 (s, 1H) 7.84(d, J = 8.62 Hz, 1H) 7.94 (d, J = 9.79 Hz, 1H) 8.10 (dd, J = 6.65, 3.00Hz, 2H) 8.42 (d, J = 9.79 Hz, 1H) 8.51 (d, J = 2.78 Hz, 1H) 10.29 (s,1H). 343 (400 MHz, DMSO-d₆) □ ppm 5.98 (d, J = 2.74 Hz, 1H), 5.99 (s,2H), 6.05 (d, J = 9.39 Hz, 1H), 7.40 (d, J = 2.74 Hz, 1H), 7.58-7.64 (m,3H), 7.93 (d, J = 9.59 Hz, 1H), 8.00 (d, J = 9.78 Hz, 1H), 8.10-8.16 (m,2H), 8.46 (d, J = 9.78 Hz, 1H), 11.44 (br. s., 1H) Cmpd # 348 1H NMR(400 MHz, DMSO-d₆) □ ppm 8.70 (d, J = 2.74 Hz, 1H), 8.53 (s, 1H), 8.50(d, J = 5.28 Hz, 1H), 8.35 (d, J = 9.68 Hz, 1H), 8.21 (d, J = 0.78 Hz,1H), 8.17 (s, 1H), 7.94 (d, J = 2.64 Hz, 1H), 7.69-7.73 (m, 1H), 6.94(d, J = 5.38 Hz, 1H), 5.15 (d, J = 6.16 Hz, 2H), 3.94 (s, 3H) 351 1H NMR(400 MHz, CHLOROFORM-d) d ppm 8.66 (d, J = 1.56 Hz, 1H), 8.08 (d, J =8.51 Hz, 1H), 7.83-7.93 (m, 2H), 7.61 (s, 1H), 7.53 (d, J = 8.61 Hz,1H), 7.42 (d, J = 9.78 Hz, 1H), 7.33 (s, 1H), 6.80-6.95 (m, 3H), 4.78(s, 2H), 3.93 (s, 3H). 352 1H NMR (400 MHz, CHLOROFORM-d) d ppm 8.67 (d,J = 2.84 Hz, 1H), 8.15 (d, J = 8.51 Hz, 1H), 7.94-7.99 (m, 1H), 7.86(dd, J = 9.59 Hz, 1H), 7.62 (s, 1H), 7.56 (dd, J = 8.61 Hz, 1H),7.34-7.43 (m, 2H), 7.07 (s, 1H), 4.77 (s, 2H), 3.95 (s, 3H), 2.51 (s,3H). 355 1H NMR (400 MHz, DMSO-d₆) □ ppm 2.52 (s, 3H) 5.19 (d, J = 6.26Hz, 2H) 6.95 (d, J = 5.38 Hz, 1H) 7.71 (dd, J = 8.51, 4.11 Hz, 1H) 7.94(d, J = 9.78 Hz, 1H) 8.04 (t, J = 6.21 Hz, 1H) 8.09 (s, 1H) 8.21 (dd, J= 8.51, 1.56 Hz, 1H) 8.50 (d, J = 5.28 Hz, 1H) 8.54 (d, J = 9.78 Hz, 1H)8.79 (dd, J = 4.11, 1.56 Hz, 1H). 359 1H NMR (400 MHz, DMSO-d₆) □ ppm2.51 (s, 3H) 5.19 (d, J = 6.06 Hz, 2H) 6.96 (d, J = 5.48 Hz, 1H) 7.94(d, J = 9.68 Hz, 1H) 8.05 (dd, J = 10.03, 2.49 Hz, 1H) 8.09 (s, 1H) 8.22(s, 1H) 8.48-8.59 (m, 2H) 8.85 (d, J = 2.64 Hz, 1H) 364 1H NMR (400 MHz,DMSO-d₆) □ ppm 2.51 (s, 3H) 5.17 (d, J = 6.16 Hz, 2H) 6.94 (d, J = 5.38Hz, 1H) 7.53 (t, J = 73.21 Hz, 1H) 7.89-7.99 (m, 2H) 8.09 (s, 1H) 8.12(t, J = 6.26 Hz, 1H) 8.51 (d, J = 5.28 Hz, 1H) 8.54 (d, J = 9.68 Hz, 1H)8.70 (d, J = 2.74 Hz, 1H). 365 1H NMR (400 MHz, DMSO-d₆) □ ppm 2.52 (s,3H) 3.33 (s, 3H) 3.71-3.76 (m, 2H) 4.27-4.31 (m, 2H) 5.14 (d, J = 6.16Hz, 2H) 6.82 (d, J = 5.38 Hz, 1H) 7.59 (d, J = 2.74 Hz, 1H) 7.94 (d, J =9.78 Hz, 2H) 8.09 (s, 1H) 8.41 (d, J = 5.28 Hz, 1H) 8.49-8.57 (m, 2H)370 1H NMR (400 MHz, MeOH) □ ppm 3.44 (s, 3H) 3.82-3.87 (m, 2H)4.29-4.34 (m, 2H) 5.40 (s, 2H) 7.02 (d, J = 5.97 Hz, 1H) 7.19-7.27 (m,1H) 7.51 (d, J = 2.64 Hz, 1H) 7.75-7.86 (m, 2H) 7.95 (d, J = 9.88 Hz,1H) 8.33 (d, J = 9.88 Hz, 1H) 8.39 (d, J = 6.26 Hz, 1H) 8.59 (s, 1H) 3711H NMR (400 MHz, DMSO-d₆) □ ppm 5.02 (q, J = 8.80 Hz, 2H) 5.22 (d, J =6.26 Hz, 2H) 6.91 (d, J = 5.48 Hz, 1H) 7.53 (t, J = 9.15 Hz, 1H) 7.79(d, J = 2.64 Hz, 1H) 7.99-8.10 (m, 3H) 8.21 (t, J = 5.97 Hz, 1H) 8.44(d, J = 5.28 Hz, 1H) 8.51 (d, J = 9.78 Hz, 1H) 8.61 (d, J = 2.64 Hz, 1H)372 1H NMR (400 MHz, DMSO-d₆) □ ppm 2.52 (s, 3H) 5.02 (q, J = 8.90 Hz,2H) 5.15 (d, J = 6.16 Hz, 2H) 6.87 (d, J = 5.38 Hz, 1H) 7.80 (d, J =2.84 Hz, 1H) 7.94 (d, J = 9.78 Hz, 1H) 8.01 (t, J = 6.11 Hz, 1H) 8.09(s, 1H) 8.45 (d, J = 5.28 Hz, 1H) 8.54 (d, J = 9.78 Hz, 1H) 8.62 (d, J =2.84 Hz, 1H). 383 1H NMR (400 MHz, DMSO-d₆) □ ppm 3.94 (s, 3H) 4.50-4.62(m, 2H) 5.14 (d, J = 6.16 Hz, 2H) 6.30-6.64 (m, 1H) 6.87 (d, J = 5.48Hz, 1H) 7.66-7.74 (m, 2H) 8.06 (t, J = 6.11 Hz, 1H) 8.21 (d, J = 0.68Hz, 1H) 8.34 (d, J = 9.68 Hz, 1H) 8.44 (d, J = 5.38 Hz, 1H) 8.52 (s, 1H)8.59 (d, J = 2.84 Hz, 1H). 390 (400 MHz, DMSO-d6) □ ppm 8.64 (s, 1H),8.51 (d, J = 2.8 Hz, 1H), 8.40 (d, J = 5.2 Hz, 1H), 8.35 (d, J = 9.6 Hz,1 Hz), 8.19 (s, 1H), 7.99 (t, J = 6.0 Hz, 1H), 7.72 (d, J = 10 Hz, 1H),7.57 (d J = 2.8 Hz, 1H), 6.83 (d, J = 5.2 Hz, 1H), 5.12 (d, J = 6.0 Hz,2H), 3.93 (s, 3H), 3.80-3.86 (m, 1H), 1.10-1015 (m, 2H), 1.00-1.08 (m,2H). 399 1H NMR (400 MHz, DMSO-d₆) d ppm 8.49-8.55 (m, 2H), 8.41 (d, J =5.38 Hz, 1H), 8.24 (s, 1H), 8.03 (d, J = 9.68 Hz, 1H), 7.94 (t, J = 6.16Hz, 1H), 7.58 (d, J = 2.84 Hz, 1H), 6.83 (d, J = 5.38 Hz, 1H), 5.67 (t,J = 5.77 Hz, 1H), 5.15 (d, J = 6.16 Hz, 2H), 4.63 (d, J = 5.67 Hz, 2H),3.93 (s, 3H). 400 1H NMR (400 MHz, DMSO-d₆) □ ppm 5.26 (d, J = 6.36 Hz,2H) 7.02 (d, J = 5.38 Hz, 1H) 7.96-8.10 (m, 2H) 8.22-8.32 (m, 2H)8.48-8.57 (m, 3H) 8.85 (d, J = 2.84 Hz, 1H) 405 1H NMR (400 MHz,DMSO-d₆) □ ppm 3.43-3.53 (m, 4H) 3.70-3.80 (m, 4H) 3.94 (s, 3H) 5.16 (d,J = 6.16 Hz, 2H) 6.85 (d, J = 5.28 Hz, 1H) 7.57 (d, J = 2.74 Hz, 1H)7.87 (s, 1H) 7.90 (d, J = 9.68 Hz, 1H) 8.01-8.08 (m, 1H) 8.35-8.45 (m,2H) 8.52 (d, J = 2.64 Hz, 1H) 406 1H NMR (400 MHz, DMSO-d₆) □ ppm 3.94(s, 3H) 5.19 (d, J = 6.26 Hz, 2H) 6.85 (d, J = 5.38 Hz, 1H) 7.57 (d, J =2.93 Hz, 1H) 7.97-8.02 (m, 1H) 8.05 (d, J = 9.78 Hz, 1H) 8.42 (d, J =5.28 Hz, 1H) 8.45 (d, J = 9.68 Hz, 1H) 8.52 (d, J = 2.84 Hz, 1H) 8.71(d, J = 1.96 Hz, 1H) 9.36 (d, J = 1.96 Hz, 1H) 408 1H NMR (400 MHz,DMSO-d₆) □ ppm 1.90 (d, J = 7.04 Hz, 3H) 2.44 (s, 3H) 5.24 (q, J = 7.01Hz, 1H) 7.51 (dd, J = 8.27, 4.16 Hz, 1H) 7.64-7.73 (m, 2H) 7.81 (dd, J =8.75, 2.01 Hz, 1H) 7.94 (d, J = 1.96 Hz, 1H) 8.00 (d, J = 8.61 Hz, 1H)8.32 (d, J = 8.41 Hz, 1H) 8.64 (d, J = 1.17 Hz, 1H) 8.86 (dd, J = 4.16,1.71 Hz, 1H) 409 1H NMR (400 MHz, DMSO-d₆) □ ppm 1.92 (d, J = 7.14 Hz,3H) 5.26 (q, 1H) 7.31 (t, J = 9.29 Hz, 1H) 7.49 (dd, J = 8.36, 4.16 Hz,2H) 7.55 (d, J = 8.61 Hz, 1H) 7.77-7.86 (m, J = 8.22 Hz, 2H) 7.95 (s,1H) 7.99 (d, J = 8.71 Hz, 1H) 8.31 (d, J = 7.24 Hz, 1H) 8.68 (s, 1H)8.85 (dd, J = 4.11, 1.66 Hz, 1H) 411 1H NMR (400 MHz, DMSO-d₆) □ ppm1.89 (d, J = 7.04 Hz, 3H) 2.27 (s, 3H) 3.88 (s, 3H) 5.22 (q, J = 6.98Hz, 1H) 6.99 (s, 1H) 7.63 (dd, J = 8.71, 2.05 Hz, 1H) 7.67-7.70 (m, 1H)7.72 (d, J = 1.86 Hz, 1H) 7.76 (dd, J = 11.54, 1.17 Hz, 1H) 7.93 (d, J =8.61 Hz, 1H) 8.58 (d, J = 2.93 Hz, 1H) 8.64 (d, J = 1.08 Hz, 1H) 413 1HNMR (400 MHz, DMSO-d₆) □ ppm 2.40 (s, 3H) 2.44 (d, J = 23.28 Hz, 3H)7.56-7.61 (m, 2H) 7.75 (dd, J = 8.90, 2.15 Hz, 1H) 7.80 (dd, J = 11.49,1.22 Hz, 1H) 8.02 (d, J = 0.88 Hz, 1H) 8.09 (d, J = 8.90 Hz, 1H) 8.12(d, J = 2.05 Hz, 1H) 8.43-8.47 (m, 1H) 8.95 (dd, J = 4.21, 1.76 Hz, 1H418 1H NMR (400 MHz, DMSO-d₆) □ ppm 3.89 (s, 3H) 4.88 (s, 2H) 7.61 (dd,J = 8.56, 2.01 Hz, 1H) 7.68 (d, J = 2.74 Hz, 1H) 7.70-7.75 (m, 1H) 7.83(s, 1H) 7.89 (dd, J = 11.44, 1.08 Hz, 1H) 7.93 (d, J = 8.61 Hz, 1H) 8.59(d, J = 2.84 Hz, 1H) 9.17 (d, J = 1.08 Hz, 1H) 430 1H NMR (400 MHz,DMSO-d₆) □ ppm 8.84 (dd, J = 4.25, 1.71 Hz, 1H), 8.42-8.46 (m, 1H), 8.26(d, J = 2.05 Hz, 1H), 8.15 (d, J = 9.49 Hz, 1H), 7.94 (s, 1H), 7.90 (d,J = 8.80 Hz, 1H), 7.67-7.76 (m, 4H), 7.52 (dd, J = 8.26, 4.25 Hz, 1H),7.38-7.44 (m, 1H), 7.32-7.37 (m, 2H), 6.17 (s, 1H), 2.17 (s, 3H) 431 1HNMR (400 MHz, DMSO-d₆) □ ppm 8.85 (dd, J = 4.21, 1.76 Hz, 1H), 8.31-8.35(m, 1H), 8.21 (d, J = 9.59 Hz, 1H), 8.04-8.08 (m, 2H), 7.95-7.99 (m,2H), 7.75-7.83 (m, 3H), 7.49-7.58 (m, 4H), 4.62 (s, 2H) 433 1H NMR (400MHz, DMSO-d₆) □ ppm 9.01 (dd, J = 4.21, 1.66 Hz, 1H), 8.54-8.59 (m, 1H),8.47 (s, 1H), 8.44 (d, J = 9.59 Hz, 1H), 8.16 (d, J = 8.80 Hz, 1H), 8.13(s, 1H), 8.00 (dd, J = 8.90, 2.05 Hz, 1H), 7.88 (d, J = 9.59 Hz, 1H),7.64 (dd, J = 8.31, 4.21 Hz, 1H), 7.11 (s, 1H), 2.33 (s, 3H) 436 1H NMR(400 MHz, DMSO-d₆) □ ppm 8.46 (d, J = 2.74 Hz, 1H), 8.38 (d, J = 5.38Hz, 1H), 8.29 (d, J = 9.39 Hz, 1H), 8.00 (s, 1H), 7.76-7.82 (m, 3H),7.54 (d, J = 2.84 Hz, 1H), 6.79 (d, J = 5.38 Hz, 1H), 4.98 (d, J = 6.36Hz, 2H), 3.91 (s, 3H) 437 ¹H NMR (400 MHz, CHLOROFORM-d) □ ppm 4.80 (s,2H) 7.19 (dd, J = 10.76, 1.17 Hz, 1H) 7.31-7.35 (m, 2H) 7.38-7.43 (m,4H) 7.65-7.71 (m, 3H) 8.07 (dd, J = 8.31, 0.88 Hz, 1H) 8.11 (d, J = 8.41Hz, 1H) 8.91 (dd, J = 4.21, 1.66 Hz, 1H). 438 ¹H NMR (400 MHz, DMSO-d₆)□ ppm 3.88 (s, 3H) 4.76 (s, 2H) 7.52-7.59 (m, 1H) 7.61 (s, 1H) 7.65 (d,J = 12.32 Hz, 1H) 7.80 (s, 1H) 7.91 (d, J = 8.80 Hz, 1H) 8.01 (s, 1H)8.27 (s, 1H) 8.57-8.66 (m, 2H) 10.59 (br. s., 1H) 439 1H NMR (400 MHz,DMF) □ ppm 7.69 (tt, J = 9.32, 2.27 Hz, 3H) 7.99 (dd, J = 8.31, 4.21 Hz,1H) 8.01-8.09 (m, 2H) 8.43 (dd, J = 8.90, 2.15 Hz, 1H) 8.54 (d, J = 8.8Hz 1H) 8.83-8.95 (m, 2H) 9.19 (d, J = 2.25 Hz, 1H) 9.37 (dd, J = 4.25,1.71 Hz, 1H) 9.53 (d, J = 2.25 Hz, 1H). MS m/z = 410.0 [M + 1]⁺ Calc'dfor C₂₂H₁₁F₄N₃O: 409.3. 442 1H NMR (400 MHz, DMSO-d₆) □ ppm 4.00 (s, 3H)5.24 (d, J = 5.97 Hz, 2H) 5.76 (d, J = 46.46 Hz, 2H) 7.64 (d, J = 2.74Hz, 1H) 7.77 (s, 1H) 8.01 (d, J = 9.68 Hz, 1H) 8.10 (t, J = 6.26 Hz, 1H)8.48 (d, J = 5.28 Hz, 1H) 8.59 (d, J = 2.74 Hz, 1H) 8.64 (d, J = 9.68Hz, 1H). 443 1H NMR (400 MHz, DMSO-d₆) □ ppm 2.40-2.40 (m, 1H) 7.58 (dd,J = 8.31, 4.21 Hz, 1H) 7.81 (s, 1H) 8.00 (dd, J = 8.90, 2.25 Hz, 1H)8.12 (d, J = 8.90 Hz, 1H) 8.44 (d, J = 1.27 Hz, 1H) 8.47 (dd, J = 8.46,1.03 Hz, 1H) 8.70 (d, J = 2.25 Hz, 1H) 8.95 (dd, J = 4.26, 1.71 Hz, 1H)9.07 (d, J = 2.15 Hz, 1H). 444 1H NMR (400 MHz, DMSO-d₆) □ ppm 7.44-7.53(m, 1H) 7.68 (dd, J = 8.31, 4.21 Hz, 1H) 8.00 (td, J = 7.78, 1.76 Hz,1H) 8.11 (dd, J = 8.90, 2.05 Hz, 1H) 8.25 (dd, J = 15.60, 8.36 Hz, 2H)8.55 (s, 1H) 8.58 (dd, J = 8.41, 0.78 Hz, 1H) 8.75 (dq, J = 4.77, 0.82Hz, 1H) 9.01-9.11 (m, 2H) 9.53 (d, J = 2.15 Hz, 1H). 450 1H NMR (400MHz, DMSO-d₆) □ ppm 7.35-7.45 (m, 1H) 7.67 (dd, J = 8.31, 4.21 Hz, 1H)7.73-7.85 (m, 2H) 8.11 (dd, J = 8.9, 2.0 Hz, 1H) 8.21 (d, J = 8.90 Hz,1H) 8.48 (d, J = 9.10 Hz, 1H) 8.57 (s, 1H) 8.60 (m, 2H) 9.04 (dd, J =4.11, 1.56 Hz, 1H). 460 1H NMR (400 MHz, DMSO-d₆) □ ppm 3.89 (s, 3H);3.89 (s, 3H); 4.01-4.02 (m, 1H); 7.86 (dd, J = 8.8, 2.2 Hz, 1H); 7.91(dd, J = 12.0, 1.0 Hz, 1H); 7.95 (d, J = 2.7 Hz, 1H); 8.11 (d, J = 0.7Hz, 1H); 8.15 (d, J = 8.7 Hz, 1H); 8.32 (d, J = 1.5 Hz, 1H); 8.56 (d, J= 0.7 Hz, 1H); 8.78 (d, J = 2.9 Hz, 1H) 462 1H NMR (400 MHz, DMSO-d₆) □ppm 1.93-2.07 (m, 2H) 2.30-2.42 (m, 4H) 2.43-2.49 (m, 2H) 3.50-3.65 (m,4H) 3.89 (s, 3H) 4.20 (t, J = 6.41 Hz, 2H) 7.86 (dd, J = 8.75, 1.91 Hz,1H) 7.96 (s, 1H) 7.98 (d, J = 2.64 Hz, 1H) 8.13 (s, 1H) 8.15 (d, J =8.90 Hz, 1H) 8.32 (s, 1H) 8.46 (s, 1H 8.57 (s, 1H) 8.78 (d, J = 2.84 Hz,1H) 468 1H NMR (400 MHz, CHLOROFORM-d) □ ppm 2.41 (s, 3H); 3.97 (s, 3H);6.54 (s, 1H); 7.39 (dd, J = 9.8, 1.2 Hz, 1H); 7.47 (d, J = 2.8 Hz, 1H);7.83 (dd, J = 8.8, 2.1 Hz, 1H); 8.17 (d, J = 1.1 Hz, 1H); 8.21 (d, J =8.7 Hz, 1H) 8.75-8.84 (m, 2H) 469 1H NMR (400 MHz, DMSO-d₆) □ ppm 3.95(s, 3H); 7.83-7.92 (m, 2H); 7.93-8.03 (m, 2H); 8.18 (d, J = 5.6 Hz, 1H);8.34 (s, 1H); 8.69 (s, 1H); 8.80 (d, J = 2.93 Hz, 1H) 470 1H NMR (400MHz, DMSO-d₆) □ ppm 2.34 (s, 3H); 7.26 (s, 1H); 7.69 (dd, J = 8.3, 4.2Hz, 1H); 8.05 (dd, J = 8.8, 2.2 Hz, 1H); 8.09 (dd, J = 11.3, 1.1 Hz,1H); 8.25 (d, J = 8.9 Hz, 1H); 8.50 (d, J = 1.7 Hz, 1H); 8.60 (s, 1H);8.80 (d, J = 1.0 Hz, 1H); 9.08 (dd, J = 4.3, 1.7 Hz, 1H) 471 1H NMR (400MHz, DMSO-d₆) □ ppm 3.70 (s, 3H); 7.57-7.67 (m, 1H); 7.72 (s, 1H);7.87-8.16 (m, 3H); 8.29 (s, 1H); 8.55 (s, 1H); 8.70 (s, 1H) 473 1H NMR(400 MHz, DMSO-d₆) □ ppm 2.32 (s, 3H); 3.47 (s, 1H); 3.55 (dd, J = 11.4, 2.01 Hz, 1H); 3.67 (s, 2H); 3.80 (s, 1H); 3.89 (s, 1H); 3.98 (s,1H); 4.16 (d, J = 5.0 Hz, 2H); 7.22 (s, 1H); 7.87 (dd, J = 8.9, 2.0 Hz,1H); 7.98 (d, J = 2.8 Hz, 1H); 8.05 (dd, J = 11.3, 0.6 Hz, 1H); 8.16 (d,J = 8.8 Hz, 1H); 8.31 (s, 1H); 8.74 (s, 1H); 8.81 (d, J = 2.9 Hz, 1H)474 1H NMR (400 MHz, DMSO-d₆) □ ppm 2.35 (s, 3H); 3.94 (s, 3H); 4.79 (d,J = 5.97 Hz, 2H); 6.76 (d, J = 5.4 Hz, 1H); 7.01 (s, 1H); 7.57 (d, J =2.7 Hz, 1H); 7.89-7.94 (m, 1H); 7.93 (d, J = 8.6 Hz, 1H); 8.21 (d, J =8.6 Hz, 1H); 8.34 (s, 1H); 8.40 (d, J = 5.4 Hz, 1H); 8.51 (d, J = 2.7Hz, 1H) 475 ¹H NMR (400 MHz, DMSO-d₆) ppm 3.89 (s, 3H) 7.68 (dd, J =8.28, 4.27 Hz, 1H) 7.93 (d, J = 12.05 Hz, 1H) 8.04 (d, J = 8.53 Hz, 1H)8.13 (s, 1H) 8.23 (d, J = 8.53 Hz, 1H) 8.43-8.52 (m, 2H) 8.55-8.63 (m,2H) 9.07 (d, J = 4.02 Hz, 1H). 476 ¹H NMR (400 MHz, DMSO-d₆) d ppm7.56-7.74 (m, 2H) 7.99 (d, J = 9.03 Hz, 1H) 8.21 (d, J = 8.53 Hz, 1H)8.40 (s, 1H) 8.57 (d, J = 8.03 Hz, 1H) 8.63 (d, J = 10.04 Hz, 1H) 9.05(d, J = 4.02 Hz, 1H) 477 ¹H NMR (400 MHz, DMSO-d₆) d ppm 3.92 (s, 3H)3.94 (s, 3H) 7.80-7.87 (m, 2H) 8.01-8.07 (m, 1H) 8.11 (d, J = 9.04 Hz,1H) 8.37 (s, 1H) 8.46-8.51 (m, 2H) 8.75 (d, J = 3.01 Hz, 1H) 478 ¹H NMR(400 MHz, DMSO-d₆) d ppm 7.67 (dd, J = 8.03, 4.02 Hz, 1H) 7.80-7.89 (m,2H) 8.17 (dd, J = 13.05, 9.54 Hz, 2H) 8.54 (s, 1H) 8.60 (d, J = 8.53 Hz,1H) 8.69 (d, J = 10.04 Hz, 1H) 9.04 (d, J = 3.51 Hz, 1H) 484 ¹H NMR (400MHz, DMSO-d₆) d ppm 2.94 (t, J = 7.78 Hz, 2H) 3.03-3.14 (m, 2H) 7.44 (d,J = 8.03 Hz, 2H) 7.68 (dd, J = 8.28, 4.27 Hz, 1H) 7.85 (br. s., 2H) 7.95(d, J = 8.03 Hz, 2H) 8.05 (d, J = 8.53 Hz, 1H) 8.12 (d, J = 9.54 Hz, 1H)8.21 (d, J = 8.53 Hz, 1H) 8.49 (s, 1H) 8.57-8.66 (m, 2H) 9.05 (d, J =4.02 Hz, 1H). 490 ¹H NMR (300 MHz, CHLOROFORM-d) d ppm 2.10 (d, J = 7.16Hz, 3H) 2.55 (s, 3H) 5.04 (q, J = 6.87 Hz, 1H) 7.27-7.52 (m, 3H) 7.82(d, J = 8.62 Hz, 1H) 7.93 (s, 1H) 8.05 (d, J = 8.62 Hz, 1H) 8.15 (d, J =9.21 Hz, 2H) 8.85 (d, J = 2.63 Hz, 1H). 496 ¹H NMR (300 MHz,CHLOROFORM-d)ppm 3.58 (s, 3H) 4.78 (s, 2H) 7.48-7.63 (m, 4H) 7.66 (d, J= 8.48 Hz, 1H) 7.87 (d, J = 7.16 Hz, 1H) 7.91-8.06 (m, 3H) 8.14 (d, J =9.65 Hz, 1H) 8.47 (s, 1H). 499 ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.94(s, 3H) 4.73 (s, 2H) 7.10 (d, J = 9.65 Hz, 1H) 7.33 (d, J = 2.78 Hz, 1H)7.63 (d, J = 10.67 Hz, 1H) 7.76 (s, 1H) 8.00 (d, J = 8.48 Hz, 1H) 8.07(d, J = 9.65 Hz, 1H) 8.64 (d, J = 2.92 Hz, 1H). 501 ¹H NMR (300 MHz,MeOH) d ppm 4.05 (s, 11H) 4.82 (s, 7H) 7.40 (dd, J = 10.08, 1.46 Hz, 4H)7.81 (dd, J = 8.77, 1.90 Hz, 4H) 7.96 (d, J = 0.88 Hz, 4H) 8.05 (d, J =8.77 Hz, 4H) 8.21 (d, J = 2.78 Hz, 4H) 8.50 (d, J = 0.73 Hz, 3H) 8.85(d, J = 2.92 Hz, 4H). 502 ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.59 (s,3H) 3.93 (s, 3H) 4.77 (s, 2H) 7.34 (d, J = 2.74 Hz, 1H) 7.38 (d, J =9.68 Hz, 1H) 7.46 (s, 1H) 7.66 (dd, J = 8.61, 2.05 Hz, 1H) 7.84 (d, J =1.96 Hz, 1H) 7.98 (d, J = 8.61 Hz, 1H) 8.16 (d, J = 9.59 Hz, 1H) 8.61(d, J = 2.93 Hz, 1H).

Although the pharmacological properties of the compounds of the currentinvention vary with structural change, in general, activity possessed bythese compounds may be demonstrated in vivo. The pharmacologicalproperties of the compounds of this invention may be confirmed by anumber of pharmacological in vitro assays. The exemplifiedpharmacological assays, which follow, have been carried out with thecompounds according to the invention. The exemplified compounds of thepresent invention demonstrated a K_(i) between 20 μM and 0.1 nM.Illustrative activity values are provided in the following table.

Ex. cMet K_(i) (μM) 1 0.0070 3 0.4004 4 0.0032 12 20 13 6.6667 14 6.666717 0.0093 18 0.0066 19 1.9075 20 0.5562 21 0.8054 23 0.1329 24 0.0174 330.0732 34 0.0159 38 0.0370 39 0.0505 40 0.0075 41 4.2537 45 0.0121 500.0238 52 0.0050 53 0.0067 55 0.0009 58 2.0618 59 0.0845 61 0.3994 620.0017 66 1.2312 67 0.7584 68 0.5563 69 0.3749 70 0.0229 73 0.0128 750.0022 79 0.0834 82 0.2617 84 0.0261 85 0.0020 86 0.0024 87 20 88 0.151689 0.0079 91 0.0192 112 1.5765 118 0.0026 121 0.0054 122 0.0272 1340.1161 140 0.0052 141 0.0029 144 0.1688 148 0.0092 152 0.4837 154 0.0502164 0.1410 167 0.0733 170 0.0508 172 0.0027 176 0.0012 186 0.0062 1870.0049 199 0.0345 202 0.0024 203 0.0075 208 0.0237 209 0.0089 214 0.0176222 0.0016 226 0.0047 229 0.0402 231 0.0067 232 0.0026 279 0.0197 2810.0631 282 0.0095 283 0.0048 289 0.0526 294 0.0028 295 0.0269 296 0.0089297 0.0032 302 0.0003 306 0.0490 309 0.0020 311 0.0070 314 3.2855 3150.2199 317 0.8465 319 0.8532 321 0.2408 324 1.6093 325 20 326 0.3936 3330.1071 334 0.4160 336 0.0007 341 0.0091 343 0.7203 373 0.0001 430 0.3480437 0.0364 439 0.2531 440 0.1716 441 0.0286 447 0.0121 450 0.1823 4660.6351

Biological Testing

The efficacy of the compounds of the invention as inhibitors of HGFrelated activity is demonstrated as follows.

c-Met Receptor Assay

Cloning, Expression and Purification of c-Met Kinase Domain

A PCR product covering residues 1058-1365 of c-Met (c-Met kinase domain)is generated from Human Liver QuickClone™ cDNA (Invitrogen) usingforward primer 5′-ATTGACGGATCCATGCTAAATCCAGAGCTGGTCCAGGCA-3′ (SEQ IDNO. 1) and reverse primer 5′-ACAACAGAATTCAATACGGAGCGACACATTTTACGTT-3′(SEQ ID NO. 2). The PCR product is cloned into a modified pFastBac1expression vector (harboring the gene for S. japonicum glutathioneS-transferase immediately upstream of the multiple cloning site) usingstandard molecular biological techniques. The GST-c-Met kinase domainfusion (GST-Met) gene is transposed into full-length baculovirus DNAusing the BacToBac™ system (Invitrogen). High5 cells are infected withthe recombinant baculovirus for 72 h at 27° C. The infected cells areharvested by centrifugation and the pellet is stored at −80° C. Thepellet is resuspended in buffer A (50 mM HEPES, pH 8.0, 0.25 M NaCl, 10mM 2-mercaptoethanol, 10% (w/v) glycerol, 0.5% (v/v) protease inhibitorcocktail (Sigma P8340), stirred at 4° C. to homogeneity, and the cellsare disrupted by microfluidization (Microfluidics) at 10,000 psi. Theresulting lysate is centrifuged at 50,000×g for 90 min at 4° C., and thesupernatant is adsorbed onto 10 mL of glutathione Sepharose™ 4B(Amersham) by batch method. The slurry is rocked gently overnight at 4°C. The glutathione resin is harvested by centrifugation and washed threetimes with 40 mL buffer A by batch method. The resin is washed threetimes with buffer B (buffer A adjusted to 0.1 M NaCl, less proteaseinhibitors). The protein is eluted with buffer B containing 25 mMreduced glutathione. Eluted fractions are analyzed by SDS-PAGE andconcentrated to <10 mL (˜10 mg/mL total protein). The concentratedprotein is separated by Superdex™ 200 (Amersham) size exclusionchromatography in buffer C (25 mM Tris, pH 7.5, 0.1 M NaCl, 10 mM2-mercaptoethanol, 10% glycerol). The fractions are analyzed by SDS-PAGEand the appropriate fractions are pooled and concentrated to ˜1 mg/mL.The protein is aliquotted and stored at −80° C.

Alternative Purification of Human GST-Cmet from Baculovirus Cells

Baculovirus cells are broken in 5× (volume/weight) of Lysis Buffer (50mM HEPES, pH 8.0, 0.25 M NaCl, 5 mM mercaptoethanol, 10% glycerol plusComplete Protease Inhibitors (Roche (#10019600), 1 tablet per 50 mLbuffer). The lysed cell suspension is centrifuged at 100,000×g (29,300rpm) in a Beckman ultracentrifuge Ti45 rotor for 1 h. The supernatant isincubated with 10 ml of Glutathione Sepharose 4B from AmershamBiosciences (#27-4574-01). Incubation is carried out overnight in a coldroom (approximately 8° C.). The resin and supernatant is poured into anappropriately sized disposable column and the flow through supernatantwas collected. The resin is washed with 10 column volumes (100 mL) ofLysis Buffer. The GST-cMET is eluted with 45 mL of 10 mM Glutathione(Sigma #G-4251) in Lysis Buffer. The elution is collected as 15 mLfractions. Aliquots of the elution fractions are run on SDS PAGE (12%Tris Glycine gel, Invitrogen, #EC6005BOX). The gel is stained with 0.25%Coomassie Blue stain. Fractions with GST-cMET are concentrated with aVivaspin 20 mL Concentrator (#VS2002; 10,00 MW cutoff) to a final volumeless than 2.0 ml. The concentrated GST-cMET solution is applied to aSuperdex 75 16/60 column (Amersham Biosciences #17-1068-01) equilibratedwith 25 mM Tris, pH 7.5, 100 mM NaCl, 10 mM mercaptoethanol, 10%glycerol. The GST-cMET is eluted with an isocratic run of the abovebuffer, with the eluent collected in 1.0 mL fractions. Fractions withsignificant OD₂₈₀ readings are run on another 12% Tris Glycine gel. Thepeak tubes with GST-cMET are pooled and the OD₂₈₀ is read with thecolumn buffer listed above as the blank buffer.

Phosphorylation of the purified GST-cMET is performed by incubating theprotein for 3 h at RT with the following:

Final concentration a) 100 mM ATP (Sigma #A7699) 25 mM b) 1.0 M MgCl₂(Sigma #M-0250) 100 mM c) 200 mM Sodium Orthovanadate (Sigma #S-6508) 15mM d) 1.0 M Tris-HCl, pH 7.00 (in house) 50 mM e) H₂0 f) GST-cMET0.2-0.5 mg/mL

After incubation, the solution is concentrated in a Vivaspin 20 mlConcentrator to a volume less than 2.00 ml. The solution is applied tothe same Superdex 75 16/60 column used above after re-equilibration. TheGST-cMET is eluted as described above. The elution fractionscorresponding to the first eluted peak on the chromatogram are run on a12% Tris Glycine gel, as above, to identify the fractions with GST-cMET.Fractions are pooled and the OD₂₈₀ is read with the column buffer usedas the blank.

A Kinase reaction Buffer is prepared as follows:

Per 1 L 60 mM HEPES _(P)H 7.4 1 M stock 16.7 X 60 mL 50 mM NaCl 5 Mstock 100 X 10 mL 20 mM MgCl₂ 1 M stock 50 X 20 mL  5 mM MnCl₂ 1 M stock200 X  5 mL

When the assay is carried out, freshly add:

2 mM DTT 1 M stock 500 X 0.05% BSA 5% stock 100 X 0.1 mM Na₃OV₄ 0.1 Mstock 1000 X 

The HTRF buffer contains:

50 mM Tris-HCl (pH 7.5), 100 mM NaCl, 0.1% BSA, 0.05% Tween 20, 5 mMEDTA

Fresh add SA-A PC (PJ25S Phycolink Streptavidin-AllophycocyaninConjugate, Prozyme Inc.) and Eu-PT66 (Eu-W1024 labeledanti-phosphorotyrosine antibody PT66, AD0069, Lot 168465, Perkin-ElmerInc.) to reach the final concentration:

-   -   0.1 nM final Eu-PT66    -   11 nM final SA-APC

Methods:

1. Dilute GST-cMet (P) enzyme in kinase buffer as follows:

Prepare 8 nM GST-cMet (P) working solution (7.32 μM to 8 nM, 915×, 10 μLto 9.15 mL). In a 96 well clear plate [Costar # 3365] add 100 μL ineleven columns, in one column add 100 μL kinase reaction buffer alone.

2. Assay plate preparation:

Use Biomek FX to transfer 10 μL 8 nM GST-cMet (P) enzyme, 48.4 μL kinasereaction buffer, 1.6 μL compound (in DMSO) (Start concentration at 10mM, 1 mM and 0.1 mM, sequential dilution 1:3 to reach 10 test points) ina 96 well costar clear plate [Costar # 3365], mix several times. Thenincubate the plate at RT for 30 min.

3. Prepare Gastrin and ATP working solution in kinase reaction buffer asfollows:

Prepare 4 μM Gastrin and 16 μM ATP working solution

Per 10 mL Gastrin 4 μM stock (500 μM to 4 μM, 125 X)  80 μL ATP 16 μMstock (1000 μM to 16 μM, 160 μL 62.5 X)

Use Biomek FX to add 20 μl ATP and Gastrin working solution to the assayplate to start reaction, incubate the plate at RT for 1 h.

4. Transfer 5 μL reaction product at the end of 1 h into 80 μL HTRFbuffer in black plate [Costar # 3356], read on Discover after 30 minincubation.

Assay Condition Summary:

K_(M) ATP* 6 μM [ATP] 4 μM K_(M) Gastrin/p(EY) 3.8 μM [gastrin] 1 μM[enzyme] 1 nM

K_(M) ATP, K_(M) gastrin for various enzymes were determined by HTRF/³³Plabeling and HTRF methods.

Examples 1-28, 30, 33-34, 36-37, AND 39-48 exhibited activity with IC₅₀values less than 0.5 μM.

c-Met Cell-Based Autophosphorylation Assay

Human PC3 and mouse CT26 cells are available obtained from ATCC. Thecells were cultured in a growth medium containing RPMI 1640,penicillin/streptomycin/glutamine (1×) and 5% FBS. 2×10⁴ cells in mediumwere plated per well in a 96 well plate and incubated at 37° C.overnight. The cells were serum-starved by replacing the growth mediawith basic medium (DMEM low glucose+0.1 BSA, 120 μL per well) at 37° C.for 16 h. Compounds (either 1 mM and 0.2 mM) in 100% DMSO were seriallydiluted (1:3) 3333 fold on a 96 well plate, diluting 1:3 with DMSO fromcolumn 1 to 11 (columns 6 and 12 receive no compound). Compound samples(2.4 μL per well) were diluted with basic medium (240 μL) in a 96 wellplate. The cells were washed once with basic medium (GIBCO, DMEM11885-076) then compound solution was added (100 μL). The cells wereincubated at 37° C. for 1 h. A (2 mg/mL) solution of CHO-HGF (7.5 μL)was diluted with 30 mL basic medium to provide a final concentration of500 ng/mL. This HGF-containing media (120 μL) was transferred to a 96well plate. Compounds (1.2 μL) was added to the HGF-containing media andmixed well. The mixture of media/HGF/compound (100 μL) was added to thecells (final HGF concentration-250 ng/mL) then incubated at 37° C. for10 min. A cell lysate buffer (20 mL) was prepared containing 1% TritonX-100, 50 mM Tris pH 8.0, 100 mM NaCl, Protease inhibitor (Sigma,#P-8340) 200 μL, Roche Protease inhibitor (Complete, # 1-697-498) 2tablets, Phosphatase Inhibitor II (Sigma, #P-5726) 200 μL, and a sodiumvanadate solution (containing 900 μL PBS, 100 μL 300 mM NaVO₃, 6 μLH₂O₂(30% stock) and stirred at RT for 15 min) (90 μL). The cells were washedonce with ice cold 1×PBS (GIBCO, #14190-136), then lysis buffer (60 μL)was added and the cells were incubated on ice for 20 min.

The IGEN assay was performed as follows: Dynabeads M-280 streptavidinbeads were pre-incubated with biotinylated anti-human HGFR(240 μLanti-human-HGFR(R&D system, BAF527 or BAF328) @ 100 μg/mL+360 μL Beads(IGEN #10029±5.4 μL buffer—PBS/1% BSA/0.1% Tween20) by rotating for 30min at RT. Antibody beads (25 μL) were transferred to a 96 well plate.Celllysate solution (25 μL) was transferred added and the plate wasshaken at RT for 1 h. Anti-phosphotyrosine 4G10 (Upstate 05-321) (19.7μL antibody+6 mL 1×PBS) (12.5 μL) was added to each well, then incubatedfor 1 h at RT. Anti-mouse IgG ORI-Tag (ORIGEN #110087) (24 μL Antibody+6mL buffer) (12.5 μL) was added to each well, then incubated at RT for 30min. 1×PBS (175 μL) was added to each well and theelectrochemiluminescence was read by an IGEN M8. Raw data was analyzedusing a 4-parameter fit equation in XLFit. IC₅₀ values are thendetermined using Grafit software. Examples 2, 4, 6-8, 11, 13, 15-21,23-26, 36-37, 39, 41, and 43-44 exhibited activity in PC3 cells withIC₅₀ values less than 1.0 μM. Examples 2, 4, 6-8, 11-13, 15-21, 23-26,36-37, 41, and 43-44 exhibited activity in CT26 cells with IC₅₀ valuesless than 1.0 μM.

rHu-bFGF: Stock concentration of 180 ng/μL: R&D rHu-bFGF: Added 139 μLof the appropriate vehicle above to the 25 μg vial lyophilized vial.13.3 μL of the [180 ng/μL] stock vial and added 26.6 μL of vehicle toyield a final concentration of 3.75 μM concentration.

Nitro-cellulose disk preparation: The tip of a 20-gauge needle was cutoff square and beveled with emery paper to create a punch. This tip wasthen used to cut out ≅0.5 mm diameter disks from a nitrocellulose filterpaper sheet (Gelman Sciences). Prepared disks were then placed intoEppendorf microfuge tubes containing solutions of either 0.1% BSA in PBSvehicle, 10 μM rHu-VEGF (R&D Systems, Minneapolis, Minn.), or 3.75 μMrHu-bFGF (R&D Systems, Minneapolis, Minn.) and allowed to soak for 45-60min before use. Each nitrocellulose filter disk absorbs approximately0.1 μL of solution.

In the rat micropocket assay, compounds of the present invention willinhibit angiogenesis at a dose of less than 50 mg/kg/day.

Tumor Model

A431 cells (ATCC) are expanded in culture, harvested and injectedsubcutaneously into 5-8 week old female nude mice (CD1 nu/nu, CharlesRiver Labs) (n=5-15). Subsequent administration of compound by oralgavage (10-200 mpk/dose) begins anywhere from day 0 to day 29 post tumorcell challenge and generally continues either once or twice a day forthe duration of the experiment. Progression of tumor growth is followedby three dimensional caliper measurements and recorded as a function oftime. Initial statistical analysis is done by repeated measures analysisof variance (RMANOVA), followed by Scheffe post hoc testing for multiplecomparisons. Vehicle alone (Ora-Plus, pH 2.0) is the negative control.Compounds of the present invention will be active at doses less than 150mpk.

Tumor Models

Human glioma tumor cells (U87MG cells, ATCC) are expanded in culture,harvested and injected subcutaneously into 5-8 week old female nude mice(CD1 nu/nu, Charles River Labs) (n=10). Subsequent administration ofcompound by oral gavage or by IP (10-100 mpk/dose) begins anywhere fromday 0 to day 29 post tumor cell challenge and generally continues eitheronce or twice a day for the duration of the experiment. Progression oftumor growth is followed by three dimensional caliper measurements andrecorded as a function of time. Initial statistical analysis is done byrepeated measures analysis of variance (RMANOVA), followed by Scheffepost hoc testing for multiple comparisons. Vehicle alone (captisol, orthe like) is the negative control. Compounds of the present inventionwill be active at 150 mpk.

Human gastric adenocarcinoma tumor cells (MKN45 cells, ATCC) areexpanded in culture, harvested and injected subcutaneously into 5-8 weekold female nude mice (CD1 nu/nu, Charles River Labs) (n=10). Subsequentadministration of compound by oral gavage or by IP (10-100 mpk/dose)begins anywhere from day 0 to day 29 post tumor cell challenge andgenerally continues either once or twice a day for the duration of theexperiment. Progression of tumor growth is followed by three dimensionalcaliper measurements and recorded as a function of time. Initialstatistical analysis is done by repeated measures analysis of variance(RMANOVA), followed by Scheffe post hoc testing for multiplecomparisons. Vehicle alone (captisol, or the like) is the negativecontrol. Compounds of the present invention will be active at 150 mpk.

Formulations

Also embraced within this invention is a class of pharmaceuticalcompositions comprising the active compounds of the current invention inassociation with one or more non-toxic, pharmaceutically-acceptablecarriers and/or diluents and/or adjuvants (collectively referred toherein as “carrier” materials) and, if desired, other activeingredients. The active compounds of the present invention may beadministered by any suitable route, preferably in the form of apharmaceutical composition adapted to such a route, and in a doseeffective for the treatment intended. The compounds and compositions ofthe present invention may, for example, be administered orally,mucosally, topically, rectally, pulmonarily such as by inhalation spray,or parentally including intravascularly, intravenously,intraperitoneally, subcutaneously, intramuscularly intrasternally andinfusion techniques, in dosage unit formulations containing conventionalpharmaceutically acceptable carriers, adjuvants, and vehicles.

The pharmaceutically active compounds of this invention can be processedin accordance with conventional methods of pharmacy to produce medicinalagents for administration to patients, including humans and othermammals.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. For example, these maycontain an amount of active ingredient from about 1 to 2000 mg,preferably from about 1 to 500 mg. A suitable daily dose for a human orother mammal may vary widely depending on the condition of the patientand other factors, but, once again, can be determined using routinemethods.

The amount of compounds which are administered and the dosage regimenfor treating a disease condition with the compounds and/or compositionsof this invention depends on a variety of factors, including the age,weight, sex and medical condition of the subject, the type of disease,the severity of the disease, the route and frequency of administration,and the particular compound employed. Thus, the dosage regimen may varywidely, but can be determined routinely using standard methods. A dailydose of about 0.01 to 500 mg/kg, preferably between about 0.01 and about50 mg/kg, and more preferably about 0.01 and about 30 mg/kg body weightmay be appropriate. The daily dose can be administered in one to fourdoses per day.

For therapeutic purposes, the active compounds of this invention areordinarily combined with one or more adjuvants appropriate to theindicated route of administration. If administered per os, the compoundsmay be admixed with lactose, sucrose, starch powder, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation as may be provided in adispersion of active compound in hydroxypropylmethyl cellulose.

In the case of psoriasis and other skin conditions, it may be preferableto apply a topical preparation of compounds of this invention to theaffected area two to four times a day.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin(e.g., liniments, lotions, ointments, creams, or pastes) and dropssuitable for administration to the eye, ear, or nose. A suitable topicaldose of active ingredient of a compound of the invention is 0.1 mg to150 mg administered one to four, preferably one or two times daily. Fortopical administration, the active ingredient may comprise from 0.001%to 10% w/w, e.g., from 1% to 2% by weight of the formulation, althoughit may comprise as much as 10% w/w, but preferably not more than 5% w/w,and more preferably from 0.1% to 1% of the formulation.

When formulated in an ointment, the active ingredients may be employedwith either paraffinic or a water-miscible ointment base. Alternatively,the active ingredients may be formulated in a cream with an oil-in-watercream base. If desired, the aqueous phase of the cream base may include,for example at least 30% w/w of a polyhydric alcohol such as propyleneglycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethyleneglycol and mixtures thereof. The topical formulation may desirablyinclude a compound, which enhances absorption or penetration of theactive ingredient through the skin or other affected areas. Examples ofsuch dermal penetration enhancers include DMSO and related analogs.

The compounds of this invention can also be administered by atransdermal device. Preferably transdermal administration will beaccomplished using a patch either of the reservoir and porous membranetype or of a solid matrix variety. In either case, the active agent isdelivered continuously from the reservoir or microcapsules through amembrane into the active agent permeable adhesive, which is in contactwith the skin or mucosa of the recipient. If the active agent isabsorbed through the skin, a controlled and predetermined flow of theactive agent is administered to the recipient. In the case ofmicrocapsules, the encapsulating agent may also function as themembrane.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier, it may comprise a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier, which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase, which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include Tween 60, Span 80, cetostearyl alcohol,myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryldistearate alone or with a wax, or other materials well known in theart.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties, since the solubility of theactive compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredients are dissolved or suspended insuitable carrier, especially an aqueous solvent for the activeingredients. The active ingredients are preferably present in suchformulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10%and particularly about 1.5% w/w.

Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules using one or more of the carriers or diluents mentioned for usein the formulations for oral administration or by using other suitabledispersing or wetting agents and suspending agents. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, tragacanth gum, and/or various buffers. Other adjuvants andmodes of administration are well and widely known in the pharmaceuticalart. The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water,or with cyclodextrin (ie. Captisol), cosolvent solubilization (ie.propylene glycol) or micellar solubilization (ie. Tween 80).

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employed,including synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

For pulmonary administration, the pharmaceutical composition may beadministered in the form of an aerosol or with an inhaler including drypowder aerosol.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable non-irritating excipient such as cocoabutter and polyethylene glycols that are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

The pharmaceutical compositions may be subjected to conventionalpharmaceutical operations such as sterilization and/or may containconventional adjuvants, such as preservatives, stabilizers, wettingagents, emulsifiers, buffers etc. Tablets and pills can additionally beprepared with enteric coatings. Such compositions may also compriseadjuvants, such as wetting, sweetening, flavoring, and perfuming agents.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes, which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention, which are defined, inthe appended claims.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

No unacceptable toxological effects are expected when compounds of thepresent invention are administered in accordance with the presentinvention.

All mentioned references, patents, applications and publications, arehereby incorporated by reference in their entirety, as if here written.

1. A compound of formula I

an enantiomer, a diastereomer, or a pharmaceutically acceptable saltthereof wherein J is N: W is CR^(2b); Z is —O—, or —NR⁵; Z* is —O—,—S(O)_(v)—, or —NR⁵—; R^(a), R^(b), R^(c) and R^(d) are eachindependently H, halo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl,cycloalkenyl, heterocyclo, aryl, heteroaryl, —NO₂, —CN, —NR⁵R^(5a),—OR⁴, —C(═O)R⁴, —C(═O)OR⁴; —C(═O)NR⁵R^(5a), —N(R⁵)C(═O)NR⁵R^(5a),—OC(═O)NR⁵R^(5a), —S(O)_(v)R⁴, —S(O)₂NR⁵R^(5a), —N(R⁵)SO₂R⁴ any of whichmay be optionally independently substituted with one or more R¹⁰ groupsas allowed by valence; or R^(a) and R^(b) together with the carbon atomto which they are bonded may combine to form a 3-10 membered cycloalkyl,a 3-10 membered cycloalkenyl ring, or a heterocyclo ring, any of whichmay be optionally substituted with one or more R¹⁰ groups as allowed byvalence; or R^(c) and R^(d) together with the carbon atom to which theyare bonded may combine to form a 3-10 membered cycloalkyl, a 3-10membered cycloalkenyl ring, or a heterocyclo ring, any of which may beoptionally substituted with one or more R¹⁰ groups as allowed byvalence; or R^(a) and/or R^(b) may combine with any R^(c) or R^(d) toform a partially or fully saturated 3-8 membered cycloalkyl ring orheterocyclo ring, either of which may be optionally substituted with oneor more R¹⁰ groups as allowed by valence; or R^(c) and R^(d) attached tothe same carbon atom may combine to form a carbonyl group; R¹ is aryl,heteroaryl or heterocyclo any of which may be optionally independentlysubstituted with one or more R¹⁰ groups as allowed by valence; R² iscycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, any of which may beoptionally independently substituted with one or more R¹⁰ as allowed byvalence, R^(2a), and R^(2b) and R³ are independently selected at eachoccurrence from H, halo, cyano, nitro, alkyl, haloalkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, —OR⁴,—S(O)_(v)R⁴, —C(═O)R⁴, —C(═S)R⁴, —C(═O)OR⁴, —C(═S)OR⁴, —C(═O)NR⁵R^(5a),—C(═S)NR⁵R^(5a), —N(R⁵)C(═O)NR⁵R^(5a), —N(R⁵)C(═S)NR⁵R^(5a),—N(R⁵)C(═O)R⁴, —N(R⁵)C(═S)R⁴, —OC(═O)NR⁵R^(5a), —OC(═S)NR⁵R^(5a),—SO₂NR⁵R^(5a), —N(R⁵)SO₂R⁴, —N(R⁵)SO₂NR⁵R^(5a), —N(R⁵)C(═O)OR⁴,—N(R⁵)C(═S)OR⁴, —N(R⁵)SO₂R⁴, any of which may be optionallyindependently substituted with one or more R¹⁰ groups as allowed byvalence; R⁴ is independently selected at each occurrence from H, alkyl,haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo,arylalkyl, heteroarylalkyl, heterocycloalkyl, and cycloalkylalkyl, anyof which may be optionally independently substituted as allowed byvalence with one or more R¹⁰ groups; R⁵ and R^(5a) are independentlyselected at each occurrence from H, alkyl, haloalkyl, cycloalkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, arylalkyl,heteroarylalkyl, heterocycloalkyl, and cycloalkylalkyl, any of which maybe optionally substituted as allowed by valence with one or more R¹⁰; orR⁵ and R^(5a) may combine to form a heterocyclo ring optionallysubstituted with one or more R¹⁰; R¹⁰ at each occurrence isindependently, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl,-(alkylene)_(m)-OR⁴, -(alkylene)_(m)-S(O)_(v)R⁴,-(alkylene)_(m)-NR⁵R^(5a), -(alkylene)_(m)-C(═O)R⁴,-(alkylene)_(m)-C(═S)R⁴, -(alkylene)_(m)-C(═O)OR⁴,-(alkylene)_(m)-OC(═O)R⁴, -(alkylene)_(m)-C(═S)OR⁴,-(alkylene)_(m)-C(═O)NR⁵R^(5a), -(alkylene)_(m)-C(═S)NR⁵R^(5a),-(alkylene)_(m)-N(R⁵)C(═O)NR⁵R^(5a),-(alkylene)_(m)-N(R⁵)C(═S)NR⁵R^(5a), -(alkylene)_(m)-N(R⁵)C(═O)R⁴,-(alkylene)_(m)-N(R⁵)C(═S)R⁴, -(alkylene)_(m)-OC(═O)NR⁵R^(5a),-(alkylene)_(m)-OC(═S)NR⁵R^(5a), -(alkylene)_(m)-SO₂NR⁵R^(5a),-(alkylene)_(m)-N(R⁵)SO₂R⁴, -(alkylene)_(m)-N(R⁵)SO₂NR⁵R^(5a),-(alkylene)_(m)-N(R⁵)C(═O)OR⁴, -(alkylene)_(m)-N(R⁵)C(═S)OR⁴, or-(alkylene)_(m)-N(R⁵)SO₂R⁴; wherein said alkyl, haloalkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groupsmay be further independently substituted with one or more-(alkylene)_(m)-OR⁴, -(alkylene)_(m)-S(O)_(v)R⁴,-(alkylene)_(m)-NR⁵R^(5a), -(alkylene)_(m)-C(═O)R⁴,-(alkylene)_(m)-C(═S)R⁴, -(alkylene)_(m)-C(═O)OR⁴,-(alkylene)_(m)-OC(═O)R⁴, -(alkylene)_(m)-C(═S)OR⁴,-(alkylene)_(m)-C(═O)NR⁵R^(5a), -(alkylene)_(m)-C(═S)NR⁵R^(5a),-(alkylene)_(m)-N(R⁵)C(═O)NR⁵R^(5a),-(alkylene)_(m)-N(R⁵)C(═S)NR⁵R^(5a), -(alkylene)_(m)-N(R⁵)C(═O)R⁴,-(alkylene)_(m)-N(R⁵)C(═S)R⁴, -(alkylene)_(m)-OC(═O)NR⁵R^(5a),-(alkylene)_(m)-OC(═S)NR⁵R^(5a), -(alkylene)_(m)-SO₂NR⁵R^(5a),-(alkylene)_(m)-N(R⁵)SO₂R⁴, -(alkylene)_(m)-N(R⁵)SO₂NR⁵R^(5a),-(alkylene)_(m)-N(R⁵)C(═O)OR⁴, -(alkylene)_(m)-N(R⁵)C(═S)OR⁴, or-(alkylene)_(m)-N(R⁵)SO₂R⁴; and further wherein any two R¹⁰ groupsattached to the same atom or attached to adjacent atoms may combine toform an optionally substituted 3- to 8 membered ring system; m is 0 or1; n is 0, 1 or 2; q and t are each independently 0 or 1; v is 0, 1 or2.
 2. A compound of claim 1, an enantiomer, a diastereomer, or apharmaceutically acceptable salt thereof, wherein R¹ is phenyl,naphthyl, benzodioxolyl, benzooxazolyl, benzoismazolyl, pyridinyl,pyrimidinyl, pyrazinyl, pyrimidinyl, pyrazidinyl, isoquinolinyl,quinolinyl, quinazolinyl, quinazolinonyl, quinoxalinyl, naphthyridinyl,benzotriazinyl, triazolopyridinyl, triazolopyrimidinyl,triazolopyridazinyl, imidazopyridinyl, imidazopyrimidinyl,imidazopyridazinyl, pyrrolopyridinyl, pyrrolopyrimidinyl,pyrrolopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl,pyrazolopyridazinyl, cinnolinyl, thienopyridinyl, thienopyrimidinyl,thienopyridazinyl, furopyridinyl, furopyrimidinyl, furopyrazidinyl,benzofuranyl, benzoimidazolyl, indolyl, benzoisoxazolyl, benzothiazolyl,or benzoisothiazolyl any of which may be optionally independentlysubstituted with one or more R¹⁰ groups as allowed by valence.
 3. Acompound of claim 1, an enantiomer, a diastereomer, or apharmaceutically acceptable salt thereof, wherein R² is phenyl,naphthyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,pyridinyl, tetrahydropyridinyl, pyridinonyl, pyrazinyl, pyrimidinyl,pyridazinyl, indolyl, isoindolyl, indolinyl, indolinonyl, isoidolinyl,isoindolinonyl, dihydrobenzofuranyl, dihydroisobenzofuranyl,benzofuranyl, isobenzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl,quinazolinonyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,dihydroquinolinonyl, dihydroisoquinolinonyl, quinoxalinyl,tetrahydroquinoxalinyl, benzomorpholinyl, dihydrobenzodioxinyl,imidazopyridinyl, naphthyridinyl, benzotriazinyl, triazolopyridinyl,triazolopyrimidinyl, triazolopyridazinyl, imidazopyridinyl,imidazopyrimidinyl, imidazopyridazinyl, pyrrolopyridinyl,pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrazolopyridinyl,pyrazolopyrimidinyl, pyrazolopyridazinyl, cinnolinyl, thienopyrrolyl,tetrahydrothienopyrrolyl, dihydrothienopyrrolonyl, thienopyridinyl,thienopyrimidinyl, thienopyridazinyl, furopyridinyl, furopyrimidinyl,furopyrazidinyl, benzofuranyl, benzoimidazolyl, benzoisoxazolyl,benzothiazolyl, or benzoisothiazolyl any of which may be optionallyindependently substituted with one or more R¹⁰ groups as allowed byvalence.
 4. A compound of claim 2, an enantiomer, a diastereomer, or apharmaceutically acceptable salt thereof, wherein R² is phenyl,naphthyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,pyridinyl, tetrahydropyridinyl, pyridinonyl, pyrazinyl, pyrimidinyl,pyridazinyl, indolyl, isoindolyl, indolinyl, indolinonyl, isoidolinyl,isoindolinonyl, dihydrobenzofuranyl, dihydroisobenzofuranyl,benzoffiranyl, isobenzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl,quinazolinonyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,dihydroquinolinonyl, dihydroisoquinolinonyl, quinoxalinyl,tetrahydroquinoxalinyl, benzomorpholinyl, dihydrobenzodioxinyl,imidazopyridinyl, naphthyridinyl, benzotriazinyl, triazolopyridinyl,triazolopyrimidinyl, triazolopyridazinyl, imidazopyridinyl,imidazopyrimidinyl, imidazopyridazinyl, pyrrolopyridinyl,pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrazolopyridinyl,pyrazolopyrimidinyl, pyrazolopyridazinyl, cinnolinyl, thienopyrrolyl,tetrahydrothienopyrrolyl, dihydrothienopyrrolonyl, thienopyridinyl,thienopyrimidinyl, thienopyridazinyl, furopyridinyl, furopyrimidinyl,furopyrazidinyl, benzofuranyl, benzoimidazolyl, benzoisoxazolyl,benzothiazolyl, or benzoisothiazolyl any of which may be optionallyindependently substituted with one or more R¹⁰ groups as allowed byvalence.
 5. A compound of claim 2, an enantiomer, a diastereomer, or apharmaceutically acceptable salt thereof, wherein R¹ is selected from

where m* is 0, 1, 2, 3, 4, 5 or 6, as allowed by valence.
 6. A compoundof claim 3, an enantiomer, a diastereomer, or a pharmaceuticallyacceptable salt thereof, wherein R² is an aryl, heteroaryl orheterocyelo ring system selected from

where m* is 0, 1, 2, 3, 4, 5 or 6, as allowed by valence.
 7. A compoundof claim 5, an enantiomer, a diastereomer, or a pharmaceuticallyacceptable salt thereof, wherein R² is an aryl, heteroaryl orheterocyclo ring system selected from

where m* is 0, 1, 2, 3, 4, 5 or 6, as allowed by valence.
 8. A compoundof claim 1, an enantiomer, a diastereomer, or a pharmaceuticallyacceptable salt thereof, having a formula IB


9. A compound of claim 8, an enantiomer, a diastereomer, or apharmaceutically acceptable salt thereof, wherein R¹ groups are eitherunsubstituted or independently substituted as allowed by valence withone or more halo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl,-(alkylene)_(m)-OR⁴, -(alkylene)_(m)-NR⁵R^(5a), -(alkylene)_(m)-C(═O)R⁴,-(alkylene)_(m)-C(═O)OR⁴, -(alkylene)_(m)-OC(═O)R⁴,-(alkylene)_(m)-C(═O)NR⁵R^(5a), -(alkylene)_(m)-N(R⁵)C(═O)NR⁵R^(5a),-(alkylene)_(m)-N(R⁵)C(═O)R⁴, -(alkylene)_(m)-OC(═O)NR⁵R^(5a), or-(alkylene)_(m)-N(R⁵)C(═O)OR⁴.
 10. A compound ol'claim 9, an enantiomer,a diastereomer, or a pharmaceutically acceptable salt thereof, whereinR¹ groups are selected from

where R^(10a), R^(10b), R^(10y) and R^(10z) are independently absent,halo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl,-(alkylene)_(m)-OR⁴, -(alkylene)_(m)-NR⁵R^(5a), -(alkylene)_(m)-C(═O)R⁴,-(alkylene)_(m)-C(═O)OR⁴, -(alkylene)_(m)-OC(═O)R⁴,-(alkylene)_(m)-C(═O)NR⁵R^(5a), -(alkylene)_(m)-N(R⁵)C(═O)NR⁵R^(5a),-(alkylene)_(m)-N(R⁵)C(═O)R⁴, -(alkylene)_(m)-OC(═O)NR⁵R^(5a), or-(alkylene)_(m)-N(R⁵)C(═O)OR⁴; or where R^(10a) and R^(10b) combine toform an optionally substituted 3- to 8-membered ring system.
 11. Acompound of claim 10, an enantiomer, a diastereomer, or apharmaceutically acceptable salt thereof, wherein R¹ is


12. A compound of claim 1, an enantiomer, a diastereomer, or apharmaceutically acceptable salt thereof, having the following formulaIF

wherein q is 0, 1, 2 or 3; n* is 0, 1 or 2; t* is 0 or 1 U¹, U², U³ andU⁴ are each independently C or N; Z* is —O—, —S(O)_(v), or —NH; R^(a),R^(b), R^(c) and R^(d) are each independently H, halo, alkyl, alkenyl,alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl,heteroaryl, —NO₂, —CN, —NR⁵R^(5a), —OR⁴, —C(═O)R⁴, —C(═O)OR⁴;—C(═O)NR⁵R^(5a), —N(R⁵)C(═O)NR⁵R^(5a), —OC(═O)NR⁵R^(5a), —S(O)_(v)R⁴, orR^(a) and R^(b) together with the carbon atom to which they are bondedmay combine to form a 3-10 membered cycloalkyl, a 3-10 memberedcycloalkenyl ring, or a heterocyclo ring, any of which may be optionallysubstituted with one or more R¹⁰ groups as allowed by valence; or R^(c)and R^(d) together with the carbon atom to which they are bonded maycombine to form a 3-10 membered cycloalkyl, a 3-10 membered cycloalkenylring, or a heterocyclo ring, any of which may be optionally substitutedwith one or more R¹⁰ groups as allowed by valence; or R^(a) and/or R^(b)may combine with any R^(c) or R^(d) to form a partially or fullysaturated 3-8 membered cycloalkyl ring or heterocyclo ring, either ofwhich may be optionally substituted with one or more R¹⁰ groups asallowed by valence; or R^(c) and R^(d) attached to the same carbon atommay combine to form a carbonyl group; R² is cycloalkyl, cycloalkenyl,heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkyl, any or which may be optionallyindependently substituted with one or more R¹⁰ as allowed by valence;R^(2a) and R^(2b) are independently selected from H, halo, alkyl,haloalkyl, cyano, nitro, amino, alkylamino, dialkylamino and alkoxy; R⁴is independently selected at each occurrence from H, alkyl, haloalkyl,cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, arylalkyl,heteroarylalkyl, heterocycloalkyl, and cycloalkylalkyl, any of which maybe optionally independently substituted as allowed by valence with oneor more R¹⁰ groups; R⁵ and R^(5a), are independently selected at eachoccurrence from H, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl,and cycloalkylalkyl, any of which may be optionally substituted asallowed by valence with one or more R¹⁰; or R⁵ and R^(5a) may combine toform a heterocyclo ring optionally substituted with one or more R¹⁰; R¹⁰and R^(10c) at each occurrence are independently, halo, cyano, nitro,oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkyl, -(alkylene)_(m)-OR⁴,-(alkylene)_(m)-S(O)_(v)R⁴, -(alkylene)_(m)-NR⁵R^(5a),-(alkylene)_(m)-C(═O)R⁴, heteroarylalkyl, cycloalkylalkyl,heterocycloalkyl, -(alkylene)_(m)-OR⁴, -(alkylene)_(m)-S(O)_(v)R⁴,-(alkylene)_(m)-NR⁵R^(5a), -(alkylene)_(m)-C(═O)R⁴,-(alkylene)_(m)-C(═S)R⁴, -(alkylene)_(m)-C(═O)OR⁴,-(alkylene)_(m)-OC(═O)R⁴, -(alkylene)_(m)-C(═S)OR⁴,-(alkylene)_(m)-C(═O)NR⁵R^(5a), -(alkylene)_(m)-C(═S)NR⁵R^(5a),-(alkylene)_(m)-N(R⁵)C(═O)NR⁵R^(5a),-(alkylene)_(m)-N(R⁵)C(═S)NR⁵R^(5a), -(alkylene)_(m)-N(R⁵)C(═O)R⁴,-(alkylene)_(m)-N(R⁵)C(═S)R⁴, -(alkylene)_(m)-OC(═O)NR⁵R^(5a),-(alkylene)_(m)-OC(═S)NR⁵R^(5a), -(alkylene)_(m)-SO₂NR⁵R^(5a),-(alkylene)_(m)-N(R⁵)SO₂R⁴, -(alkylene)_(m)-N(R⁵)SO₂NR⁵R^(5a),-(alkylene)_(m)-N(R⁵)C(═O)OR⁴, -(alkylene)_(m)-N(R⁵)C(═S)OR⁴, or-(alkylene)_(m)-N(R⁵)SO₂R⁴; wherein said alkyl, haloalkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groupsmay be further independently Substituted with one or more-(alkylene)_(m)-OR⁴, -(alkylene)_(m)-S(O)_(v)R⁴,-(alkylene)_(m)-NR⁵R^(5a), -(alkylene)_(m)-C(═O)R⁴,-(alkylene)_(m)-C(═S)R⁴, -(alkylene)_(m)-C(═O)OR⁴,-(alkylene)_(m)-OC(═O)R⁴, -(alkylene)_(m)-C(═S)OR⁴,-(alkylene)_(m)-C(═O)NR⁵R^(5a), -(alkylene)_(m)-C(═S)NR⁵R^(5a),-(alkylene)_(m)-N(R)C(═O)NR⁵R^(5a), -(alkylene)_(m)-N(R⁵)C(═S)NR⁵R^(5a),-(alkylene)_(m)-N(R⁵)C(═O)R⁴, -(alkylene)_(m)-N(R⁵)C(═S)R⁴,-(alkylene)_(m)-OC(═O)NR⁵R^(5a), -(alkylene)_(m)-OC(═S)NR⁵R^(5a),-(alkylene)_(m)-SO₂NR⁵R^(5a), -(alkylene)_(m)-N(R⁵)SO₂R⁴,-(alkylene)_(m)-N(R⁵)SO₂NR⁵R^(5a), -(alkylene)_(m)-N(R⁵)C(═O)OR⁴,-(alkylene)_(m)-N(R⁵)C(═S)OR⁴, or -(alkylene)_(m)-N(R⁵)SO₂R⁴; v is 0, 1or
 2. 13. A compound of claim 12, an enantiomer, a diastereomer, or apharmaceutically acceptable salt thereof, having formula IFi, IFii,IFiii or IFiv


14. A compound of claim 13, an enantiomer, a diastereomer, or apharmaceutically acceptable salt thereof, wherein R² phenyl, naphthyl,pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl,thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl,tetrahydropyridinyl, pyridinonyl, pyrazinyl, pyrimidinyl, pyridazinyl,indolyl, isoindolyl, indolinyl, indolinonyl, isoidolinyl,isoindolinonyl, dihydrobenzofuranyl, dihydroisobenzofuranyl,benzofuranyl, isobenzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl,quinazolinonyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,dihydroquinolinonyl, dihydroisoquinolinonyl, quinoxalinyl,tetrahydroquinoxalinyl, benzomorpholinyl, dihydrobenzodioxinyl,imidazopyridinyl, naphthyridinyl, benzotriazinyl, triazolopyridinyl,triazolopyrimidinyl, triazolopyridazinyl, imidazopyridinyl,imidazopyrimidinyl, imidazopyridazinyl, pyrrolopyridinyl,pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrazolopyridinyl,pyrazolopyrimidinyl, pyrazolopvridazinyl, cinnolinyl, thienopyrrolyl,tetrahydrothienopyrrolyl, dihydrothienopyrrolonyl, thienopyridinyl,thienopyrimidinyl, thienopyridazinyl, furopyridinyl, furopyrimidinyl,furopyrazidinyl, benzofuranyl, benzoimidazolyl, benzoisoxazolyl,benzothiazolyl, or benzoisothiazolyl any of which may be optionallyindependently substituted with one or more R¹⁰ groups as allowed byvalence.
 15. A compound of claim 14, an enantiomer, a diastereomer, or apharmaceutically acceptable salt thereof, wherein R² is an aryl,heteroaryl or heterocyclo ring system selected from

where m* is 0, 1, 2, 3, 4, 5 or 6, as allowed by valence.
 16. A compoundof claim 15, an enantiomer, a diastereomcr, or a pharmaceuticallyacceptable salt thereof, wherein R^(10c) at each occurrence isindependently absent, halo, cyano, nitro, alkyl, alkenyl, alkynyl,haloalkyl, -(alkylene)_(m)-OR⁴, -(alkylene)_(m)-NR⁵R^(5a),-(alkylene)_(m)-C(═O)R⁴, -(alkylene)_(m)-C(═O)OR⁴,-(alkylene)_(m)-OC(═O)R⁴, -(alkylene)_(m)-C(═O)NR⁵R^(5a),-(alkylene)_(m)-N(R⁵)C(═O)NR⁵R^(5a), -(alkylene)_(m)-N(R⁵)C(═O)R⁴,-(alkylene)_(m)-OC(═O)NR⁵R^(5a), or -(alkylene)_(m)-N(R⁵)C(═O)OR⁴.
 17. Acompound of claim 12, an enantiomer, a diastereomcr, or apharmaceutically acceptable salt thereof, wherein n* is 0 or 1, and t*is
 1. 18. A compound of claim 12, an enantiomer, a diastereomcr, or apharmaceutically acceptable salt thereof, wherein n* is 1 and t* is 0.19. A compound of claim 1, an enantiomer, a diastereomer, or apharmaceutically acceptable salt thereof, having the following formulaIFA

wherein q is 0, 1, 2 or 3; n* is 0, 1 or 2; t* is 0 or 1 U¹ U² and U³are each independently C, or N; Z* is —O—, —S(O)_(v)—, or —NH—; R^(a),R^(b), R^(c) and R^(d) are each independently H, halo, alkyl, alkenyl,alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl,heteroaryl, —NO₂, —CN, —NR⁵R^(5a), —OR⁴, —C(═O)R⁴, —C(═O)OR⁴;—C(═O)NR⁵R^(5a), —N(R⁵)C(═O)NR⁵R^(5a), —OC(═O)NR⁵R^(5a), —S(O)_(v)R⁴,—S(O)₂NR⁵R^(5a), —N(R⁵)SO₂R⁴ any of which may be optionallyindependently substituted with one or more R¹⁰ groups as allowed byvalence; or R^(a) and R^(b) together with the carbon atom to which theyare bonded may combine to form a 3-10 membered cycloalkyl, a 3-10membered cycloalkenyl ring, or a heterocyclo ring, any of which may beoptionally substituted with one or more R¹⁰ groups as allowed byvalence; or R^(c) and R^(d) together with the carbon atom to which theyare bonded may combine to form a 3-10 membered cycloalkyl, a 3-10membered cycloalkenyl ring, or a heterocyclo ring, any of which may beoptionally substituted with one or more R¹⁰ groups as allowed byvalence; or R^(a) and/or R^(b) may combine with any R^(c) or R^(d) toform a partially or fully saturated 3-8 membered cycloalkyl ring orheterocyclo ring, either of which may be optionally substituted with oneor more R¹⁰ groups as allowed by valence; or R^(C) and R^(d) attached tothe same carbon atom may combine to form a carbonyl group; R² iscycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, any of which may beoptionally independently substituted with one or more R¹⁰ as allowed byvalence, R^(a) and R^(2b) are independently selected from H, halo,alkyl, haloalkyl, cyano, nitro, amino, alkylamino, dialkylamino andalkoxy; R⁴ is independently selected at each occurrence from H, alkyl,haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo,arylalkyl, heteroarylalkyl, heterocycloalkyl, and cycloalkylalkyl, anyof which may be optionally independently substituted as allowed byvalence with one or more R¹⁰ groups; R⁵ and R^(5a) are independentlyselected at each occurrence from H, alkyl, haloalkyl, cycloalkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, arylalkyl,heteroarylalkyl, heterocycloalkyl, and cycloalkylalkyl, any of which maybe optionally substituted as allowed by valence with one or more R¹⁰; orR⁵ and R^(5a) may combine to form a heterocyclo ring optionallysubstituted with one or more R¹⁰; R¹⁰ and R^(10c) at each occurrence areindependently, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl,-(alkylene)_(m)-OR⁴, -(alkylene)_(m)-S(O)_(v)R⁴,-(alkylene)_(m)-NR⁵R^(5a), -(alkylene)_(m)-C(═O)R⁴,-(alkylene)_(m)-C(═S)R⁴, -(alkylene)_(m)-C(═O)OR⁴,-(alkylene)_(m)-OC(═O)R⁴, -(alkylene)_(m)-C(═S)OR⁴,-(alkylene)_(m)-C(═O)NR⁵R^(5a), -(alkylene)_(m)-C(═S)NR⁵R^(5a),-(alkylene)_(m)-N(R⁵)C(═O)NR⁵R^(5a),-(alkylene)_(m)-N(R⁵)C(═S)NR⁵R^(5a), -(alkylene)_(m)-N(R⁵)C(═O)R⁴,-(alkylene)_(m)-N(R⁵)C(═S)R⁴, -(alkylene)_(m)-OC(═O)NR⁵R^(5a),-(alkylene)_(m)-OC(═S)NR⁵R^(5a), -(alkylene)_(m)-SO₂NR⁵R^(5a),-(alkylene)_(m)-N(R⁵)SO₂R⁴, -(alkylene)_(m)-N(R⁵)SO₂NR⁵R⁵a,-(alkylene)_(m)-N(R⁵)C(═O)OR⁴, -(alkylene)_(m)-N(R⁵)C(═S)OR⁴, or-(alkylene)_(m)-N(R⁵)SO₂R⁴; wherein said alkyl, haloalkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groupsmay be further independently substituted with one or more-(alkylene)_(m)-OR⁴, -(alkylene)_(m)-S(O)_(v)R⁴,-(alkylene)_(m)-NR⁵R^(5a), -(alkylene)_(m)-C(═O)R⁴,-(alkylene)_(m)-C(═S)R⁴, -(alkylene)_(m)-C(═O)OR⁴,-(alkylene)_(m)-OC(═O)R⁴, -(alkylene)_(m)-C(═S)OR⁴,-(alkylene)_(m)-C(═O)NR⁵R^(5a), -(alkylene)_(m)-C(═S)NR⁵R^(5a),-(alkylene)_(m)-N(R⁵)C(═O)NR⁵R^(5a),-(alkylene)_(m)-N(R⁵)C(═S)NR⁵R^(5a), -(alkylene)_(m)-N(R⁵)C(═O)R⁴,-(alkylene)_(m)-N(R⁵)C(═S)R⁴, -(alkylene)_(m)-OC(═O)NR⁵R^(5a),-(alkylene)_(m)-OC(═S)NR⁵R^(5a), -(alkylene)_(m)-SO₂NR⁵R^(5a),-(alkylene)_(m)-N(R⁵)SO₂R⁴, -(alkylene)_(m)-N(R)SO₂NR⁵R^(5a),-(alkylene)_(m)-N(R)C(═O)OR⁴, -(alkylene)_(m)-N(R⁵)C(═S)OR⁴, or-(alkylene)_(m)-N(R⁵)SO₂R⁴; v is 0, 1 or
 2. 20. A compound of claim 19,an enantiomer, a diastereomer, or a pharmaceutically acceptable saltthereof, having formula IFAi, IFAii or IFAiii


21. A compound of claim 20, an enantiomer, a diastereomer, or apharmaceutically acceptable salt thereof, wherein R² is phenyl,naphthyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,pyridinyl, tetrahydropyridinyl, pyridinonyl, pyrazinyl, pyrimidinvl,pyridazinyl, isoindolyl, indolinyl, indolinonyl, isoidolinyl,isoindolinonyl, dihydrobenzofuranyl, dihydroisobenzofuranyl,benzofururanyl, isobenzofuranyl, quinolinyl, isoquinolinyl,quinazolinyl, quinazolinonyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl,quinoxalinyl, tetrahydroquinoxalinyl, benzomorpholinyl,dihydrobenzodioxinyl, imidazopyridinyl, naphthyridinyl, benzotriazinyl,triazolopyridinyl, triazolopyrimidinyl, triazolopyridazinyl,imidazopyridinyl, imidazopyrimidinyl, imidazopyridazinyl,pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl,pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, cinnolinyl,thienopyrrolyl, tetrahydrothienopyrrolyl, dihydrothienopyrrolonyl,thienopyridinyl, thienopyrimidinyl, thienopyridazinyl, furopyridinyl,furopyrimidinyl, furopyrazidinyl, benzofuranyl, benzoimidazolyl,benzoisoxazolyl, benzothiazolyl, or henzoisothiazolyl any of which maybe optionally independently substituted with one or more R¹⁰ groups asallowed by valence.
 22. A compound of claim 21, an enantiomer, adiastereomer, or a pharmaceutically acceptable salt thereof, wherein R²is an aryl, heteroaryl or heterocyclo ring system selected from

where m* is 0, 1, 2, 3, 4, 5 or 6, as allowed by valence.
 23. A compoundof claim 22, an enantiomer, a diastereomer, or a pharmaceuticallyacceptable salt thereof, wherein R^(10c) at each occurrence isindependently H, halo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl,-(alkylene)_(m)-OR⁴, -(alkylene)_(m)-NR⁵R^(5a), -(alkylene)_(m)-C(═O)R⁴,-(alkylene)_(m)-C(═O)R⁴, -(alkylene)_(m)-OC(═O)R⁴,-(alkylene)_(m)-C(═O)NR⁵R^(5a), -(alkylene)_(m)-N(R⁵)C(═O)NR⁵R^(5a),-(alkylene)_(m)-N(R⁵)C(═O)R⁴, -(alkylene)_(m)-OC(═O)NR⁵R^(5a), or-(alkylene)_(m)-N(R⁵)C(═O)OR⁴.
 24. A compound of claim 19, anenantiomer, a diastereomer, or a pharmaceutically acceptable saltthereof, wherein n* is 0 or 1, and t* is
 1. 25. A compound of claim 19,an enantiomer, a diastereomer, or a pharmaceutically acceptable saltthereof, wherein n* is 1 and t* is
 0. 26. A pharmaceutical compositioncomprising a compound of claim 1 together with a pharmaceuticallyacceptable vehicle or carrier.
 27. A method of treating cancer, whereincancer is glioma, or gastric cancer in a subject, said method comprisingadministering an effective amount of a compound as in claim 1, or apharmaceutically acceptable salt thereof.
 28. A compound of claim 1, anenantiomer, a diastereomer, or a pharmaceutically acceptable saltthereof, wherein R² is selected from

where m* is 0, 1, 2, 3, 4, 5 or 6, as allowed by valence.
 29. A compoundof claim 28, an enantiomer, a diastereomer, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is selected from the groupconsisting of


30. A compound of claim 28, an enantiomer, a diastereomer, or apharmaceutically acceptable salt thereof, wherein R¹⁰ is alkyl.
 31. Acompound of claim 30, an enantiomer, a diastereomer, or apharmaceutically acceptable salt thereof, wherein R^(2b) is halo.
 32. Acompound of claim 31, an enantiomer, a diastereomer, or apharmaceutically acceptable salt thereof, wherein R^(a) and R^(b) areeach independently alkyl.
 33. A compound of claim 12, an enantiomer, adiastereomer, or a pharmaceutically acceptable salt thereof, selectedfrom the group consisting of


34. A compound of claim 12, an enantiomer, a diastereomer, or apharmaceutically acceptable salt thereof, that is


35. A compound of claim 12, an enantiomer, a diastereomer, or apharmaceutically acceptable salt thereof, that is


36. A compound of claim 12, an enantiomer, a diastereomer, or apharmaceutically acceptable salt thereof, that is


37. A compound of claim 12, an enantiomer, a diastereomer, or apharmaceutically acceptable salt thereof, that is


38. A compound of claim 12, an enantiomer, a diastereomer, or apharmaceutically acceptable salt thereof, that is


39. A compound of claim 12, an enantiomer, a diastereomer, or apharmaceutically acceptable salt thereof, that is


40. A pharmaceutical composition comprising a compound as in any one ofclaims 33-39 together with a pharmaceutically acceptable vehicle orcarrier.
 41. A method of treating cancer, wherein cancer is glioma, orgastric cancer in a subject, said method comprising administering aneffective amount of a compound as in any one of claims 33-39, or apharmaceutically acceptable salt thereof
 42. A compound of claim 19, ora pharmaceutically acceptable salt thereof, selected from the groupconsisting of


43. A compound of claim 42, an enantiomer, a diastereomer, or apharmaceutically acceptable salt thereof, that is


44. A pharmaceutical composition comprising the compound of claim 43together with a pharmaceutically acceptable vehicle or carrier.
 45. Amethod of treating cancer, wherein cancer is glioma, or gastric cancerin a subject, said method comprising administering an effective amountof the compound of claim 43 or a pharmaceutically acceptable saltthereof
 46. A compound of claim 42, an enantiomer, a diastereomer, or apharmaceutically acceptable salt thereof, that is


47. A pharmaceutical composition comprising the compound of claim 46together with a pharmaceutically acceptable vehicle or carrier.
 48. Amethod of treating cancer, wherein cancer is glioma, or gastric cancerin a subject, said method comprising administering an effective amountof the compound of claim 46 or a pharmaceutically acceptable saltthereof
 49. A compound of claim 42, an enantiomer, a diastereomer, or apharmaceutically acceptable salt thereof, that is


50. A pharmaceutical composition comprising the compound of claim 49together with a pharmaceutically acceptable vehicle or carrier.
 51. Amethod of treating cancer, wherein cancer is glioma, or gastric cancerin a subject, said method comprising administering an effective amountof the compound of claim 49 or a pharmaceutically acceptable saltthereof